nutrients

Article
Link Between Metabolic Syndrome, Blood Lipid Markers,
Dietary Lipids, and Survival in Women with Early-Stage
Breast Cancer
Christine Bobin-Dubigeon 1,2,3, *, Loic Campion 2 , Clémence Bossard 1,3 , Elsa Rossignol 2 ,
Jean-Sébastien Frenel 2 , Mario Campone 2 and Jean-Marie Bard 3

1 Nantes Université CNRS, US2B, UMR 6286, 44000 Nantes, France; [email protected]
2 ICO René Gauducheau, Bd Jacques Monod, 44805 Nantes Saint Herblain CEDEX, France;
[email protected] (L.C.); [email protected] (E.R.);
[email protected] (J.-S.F.); [email protected] (M.C.)
3 Centre de Recherche en Nutrition Humaine Ouest (CRNH), 44093 Nantes, France;
[email protected]
* Correspondence: [email protected]

Abstract: Background/Objectives: Nearly 10% of cancers could be prevented through dietary changes.
In addition, breast cancer (BC) is the most common cancer in women worldwide. Inadequate diet may
lead to several metabolic abnormalities, including metabolic syndrome (MS). The goal of our study is
to evaluate the link between survival after BC and MS, as well as diet lipids and circulating lipids.
Methods: This study was performed in an early-stage BC cohort (n = 73): MS, dietary lipids, and
circulating biological parameters, including leucocyte expression in cholesterol carriers (ATP-binding
cassette transporter ABCA1, ABCG1), were determined before any medication intervention. The
data of each patient were analyzed using univariate logistic regression and are expressed by HR,
95%CI [5th–95th]. All these parameters were explored with survival parameters using Cox regression
analyses. Results: Overall survival (OS) and invasive disease-free survival (iDFS) were significantly
Citation: Bobin-Dubigeon, C.;
longer for the women without metabolic syndrome with HR 4.7 [1.11–19.92] and p = 0.036, and
Campion, L.; Bossard, C.; Rossignol, 3.58 [1.23–10.44] and p = 0.019, respectively. The expression of ABCG1 in peripheral leucocytes, an
E.; Frenel, J.-S.; Campone, M.; Bard, ATP-binding cassette transporter involved in cholesterol and phospholipid trafficking, is significantly
J.-M. Link Between Metabolic associated with iDFS (1.38 [1.1–1.9], p = 0.0048). MS is associated with more pejorative survival
Syndrome, Blood Lipid Markers, parameters in early-stage breast cancer. Paraoxonase (or PON) activities differ according to PON gene
Dietary Lipids, and Survival in polymorphism, but also diet. A link between PON activities and survival parameters was suggested
Women with Early-Stage Breast and needs to be clarified. Conclusions: This study emphasizes the link between survival parameters
Cancer. Nutrients 2024, 16, 3579. of early-stage breast cancer, metabolic syndrome, and some parameters related to lipid metabolism.
https://doi.org/10.3390/
nu16213579
Keywords: breast cancer; nutrition; lipids; paraoxonase; metabolic syndrome; dietary habits
Academic Editor: Jianjun Deng

Received: 25 July 2024

Revised: 1 October 2024
1. Introduction
Accepted: 11 October 2024
Published: 22 October 2024 Breast cancer is the most common cancer in women worldwide with more than
2.26 millions new cases diagnosed in 2020 [1]. Diet, nutrition, and physical activity affect
breast cancer risk, but also breast cancer survival and recurrence.
A diet rich in lipids may be a risk factor for many diseases, especially cardiovascular
Copyright: © 2024 by the authors. disease, but also for breast cancer [2]. However, the quality of the lipids must be taken into
Licensee MDPI, Basel, Switzerland. account. In fact, the Mediterranean diet, based on an abundant consumption of extra virgin
This article is an open access article
olive oil and foods of plant origin in particular, has been suggested to have a protective
distributed under the terms and
effect against the occurrence of breast cancer [2], especially in menopausal women [3]. A
conditions of the Creative Commons
poor lifestyle and an unbalanced and too rich a diet, associated with being overweight
Attribution (CC BY) license (https://
in postmenopausal women, are modifiable risk factors for BC, whereas being overweight
creativecommons.org/licenses/by/
seems to be associated with a lower risk in premenopausal women.
4.0/).

Nutrients 2024, 16, 3579. https://doi.org/10.3390/nu16213579 https://www.mdpi.com/journal/nutrients

Nutrients 2024, 16, 3579 2 of 13

Metabolic syndrome (MS), which has been extensively studied in the cardiovascular
context, is defined as a cluster of risk factors for cardiovascular disease (hyperglycemia,
hypertriglyceridemia, low HDL cholesterol, visceral obesity, and high blood pressure),
usually associated with hyperinsulinemia [4]. More recently, common mechanisms between
cancer and metabolic syndrome, such as inflammation, insulin resistance, and excess
adiposity, have prompted interest.
Dietary intake, especially lipid intake, may also play a role in various inflammatory
processes [5], and the impact of food intake on inflammation could be determined by
evaluating a dietary inflammation score through dietary questionnaire analyses [6].
Lipids play an important role in the development of tumors. Indeed, lipids are
important for maintaining cellular homeostasis, but they are also used to synthesize cellular
signaling molecules [7]. Among many lipid actors, we have focused for two decades on the
expression of different genes such as LXRb- and LXR-dependent proteins such as ABCA1
and ABCG1 involved in cholesterol efflux from cells [8,9]. In previous studies, we have
identified another actor of lipid metabolism, paraoxonase (PON), as a potential marker of
survival in patients with breast cancer recurrence. Its role and purpose are not completely
discovered; yet, it is commonly recognized that it plays an antioxidant role [10,11].
Moreover, its role in some diseases such as cardiovascular disease, inflammatory
disease, and cancer has been shown in previous studies. Indeed, in the main cancer localiza-
tions, plasmatic PON activities are drastically lower in patients compared to controls [10].
Diet may influence PON, as high fat intake has been shown to be associated with lower
activity of the enzyme [12], and it has also been shown that some genetic polymorphism
(L55M and Q192R) can impact PON1 activity [13,14].
The goals of our study are to evaluate the link between metabolic syndrome, blood
lipid markers, dietary lipids, and survival parameters in a cohort of patients suffering from
an early-stage breast cancer positive for hormone receptors.

2. Materials and Methods

2.1. Patients
Study Design
Eligible patients of this multicenter open-label phase 2 trial, called TAM, were women
aged 18 years or older, newly diagnosed for early-stage breast cancer (tumor size > 15 mm)
with estrogen-receptor-positive, HER2-negative operable primary cancer, without evidence
of metastatic spread. This study was carried out in accordance with the guidelines for
Good Clinical Practice and the Declaration of Helsinki and was approved by the CPP
Ouest IV (EUDRACT 2008-007652-10). Written informed consent and specific genetic
consent were obtained from each participant. The current study protocol is available online
(https://clinicaltrials.gov/ct2/show/NCT01220076, accessed on 6 July 2024). Tamoxifen
20 mg per day was prescribed for 5 weeks after enrollment, prior to breast surgery.
One of the secondary objectives was to examine the interaction of diet and tamox-
ifen treatment. Nutritional parameters such as dietary habits and circulating nutritional
biomarkers were evaluated at baseline, immediately after inclusion and before any treatment.
The flowchart of this study is summarized in Figure 1.

2.2. Metabolic Syndrome

Metabolic syndrome (MS) was defined for women according to [15] which requires
the presence of three of the five following criteria: (1) hypertriglyceridemia (~1.50 g/litre or
1.7 mmol/litre); (2) high arterial blood pressure (~130/85 mm Hg); (3) low HDL cholesterol
(<0.5 g/L or 1.1 mmol/L); (4) hyperglycemia (~1.0 g/L or 5.6 mmol/L); and (5) waist
measurement equal to or higher than 88 cm. Treatment for hypertension, hyperglycemia,
or dyslipidemia was considered a positive criterion.
Nutrients 2024, 16, x FOR PEER REVIEW
3579 3 3of
of 13

Figure
Figure 1.
1. Flowchart
Flowchart of this study.

For each Syndrome

2.2. Metabolic patient, the clinico-biological data (age, including menopausal status, weight,
height,
Metaboliccancer
breast subtype,
syndrome (MS)tumor overexpression)
was defined for women were collected
according at baseline,
to [15] prior to
which requires
any treatment, to assess the prevalence of MS. Performance status (PS, a standard criterion
the presence of three of the five following criteria: (1) hypertriglyceridemia (~1.50 g/litre
for 1.7
or measuring the impact
mmol/litre); of thearterial
(2) high diseaseblood
on a patient’s daily
pressure living abilities)
(~130/85 mm Hg); was
(3)collected
low HDL for
each patient. Overall survival (OS), invasive disease-free survival (iDFS), and relapse-free
cholesterol (<0.5 g/L or 1.1 mmol/L); (4) hyperglycemia (~1.0 g/L or 5.6 mmol/L); and (5)
survival
waist (RFS) were explored
measurement equal toin relation to MS.
or higher than 88 cm. Treatment for hypertension,
hyperglycemia,
2.3. Dietary Lipids orand
dyslipidemia was considered a positive criterion.
Lipidic Biomarkers
For each patient, the clinico-biological data (age, including menopausal status,
2.3.1. Dietary Intake
weight, height, breast cancer subtype, tumor overexpression) were collected at baseline,
priorDietary intake wasto
to any treatment, assessed at baseline
assess the prevalenceusing
of 3-day self-report questionnaires
MS. Performance (2 week-
status (PS, a standard
days and 1 weekend day) to evaluate the relationship between diet, metabolic syndrome,
criterion for measuring the impact of the disease on a patient’s daily living abilities) was
and lipid biomarkers as described [16]. This 72 h food recall provides detailed information
collected for each patient. Overall survival (OS), invasive disease-free survival (iDFS), and
on the quality and quantity of the meals consumed. For each patient, dietary intakes
relapse-free survival (RFS) were explored in relation to MS.
were converted into energy and macro- and micronutrients according to the Ciqual French
food composition table 2020 [17] by using Nutrilog software (version 3.20). Validation of
2.3. Dietary Lipids and Lipidic Biomarkers
dietary intake was performed according to the Golberg cut-off for energy intake (>1.35) as
2.3.1. Dietary
described Intake
in [18].
Dietary
A dietary intake was assessed
inflammatory score at baseline
(DII using
score) was 3-day self-report
calculated questionnaires
for each validated question-(2
weekdays and 1toweekend
naire according Shivappa’s day) to evaluate
adapted method the[6,19–21].
relationship between
The DII score diet, metabolic
was calculated
syndrome, andaccount
by taking into lipid biomarkers
the intakeas ofdescribed [16]. This
27 nutriments (total72 h foodalcohol,
energy, recall provides
vitaminsdetailed
B6 and
information on the quality
B12, beta carotene, and quantity
carbohydrates, of the meals
cholesterol, consumed.
fat, fiber, Foriron,
folic acid, eachmagnesium,
patient, dietarymo-
nounsaturated
intakes fatty acidsinto
were converted (MUFAs),
energypolyunsaturated
and macro- andfatty acids (PUFAs),
micronutrients niacin, protein,
according to the
omega French
Ciqual 3 and omega 6 fatty acids,table
food composition riboflavin, saturated
2020 [17] by usingfatty acids,software
Nutrilog selenium, thiamin,
(version vi-
3.20).
tamins A, C,
Validation of D, and E,
dietary and zinc).
intake The DII score
was performed was explored
according in relation
to the Golberg to the
cut-off forsurvival
energy
parameters
intake and
(>1.35) as the biological
described parameters related to paraoxonase activities.
in [18].
A dietary inflammatory score (DII score) was calculated for each validated
2.3.2. Circulating
questionnaire Lipids and
according Apolipoproteins
to Shivappa’s adapted method [6,19–21]. The DII score was
Total cholesterol,
calculated by taking plasma triglycerides,
into account high-density
the intake lipoprotein cholesterol
of 27 nutriments (HDL-C),
(total energy, and
alcohol,
low-density
vitamins B6 lipoprotein
and B12, beta cholesterol
carotene,(LDL-C) concentrations
carbohydrates, were measured
cholesterol, fat, fiber,atfolic
baseline
acid, using
iron,
enzymatic kits
magnesium, from Diasys® , according
monounsaturated to the
fatty acids manufacturer’s
(MUFAs), instructions
polyunsaturated fatty(Grabels, France).
acids (PUFAs),
Apolipoproteins were quantified by LC MS/MS as previously described
niacin, protein, omega 3 and omega 6 fatty acids, riboflavin, saturated fatty acids, [22].
selenium, thiamin, vitamins A, C, D, and E, and zinc). The DII score was explored in
Nutrients 2024, 16, 3579 4 of 13

2.3.3. LXR-Regulated Genes of Cholesterol Trafficking

In order to explore the LXR-regulated genes of cholesterol trafficking and lipidic
patterns, nucleic acids were extracted from Tempus blood RNA tubes (Thermo Fisher,
Nantes, France) at baseline and at week 5, as previously described [23]. Relative quantifica-
tion was performed using the ∆CT method. The genes involved in cholesterol trafficking
and studied in this work were ABCA1, ABCG1, PON2, and LXRβ. The genes and Taqman®
probes (Life Technologies, Villebon sur Yvette, France) were as follows (gene name, as-
say ID): ATP-binding cassette, sub-family A, member 1, Hs00194045_m1 for ABCA1;
ATP-binding cassette, subfamily G (WHITE), member 1 (ABCG1), Hs01555189_m1 for
ABCG1; nuclear receptor subfamily 1, group H, member 2 (NR1H2), Hs01027208_m1 for
LXRβ; and paraoxonase, Hs00165563_m1 for PON2, as described in [23]. The values were
normalized against three housekeeping genes as described previously.
The expression of these genes was explored in relation to the three survival parameters
and to the intake of dietary fatty acids.

2.3.4. Paraoxonase
At baseline, serum paraoxonase (PON1) activities were quantified on three different
substrates, paraoxon (PON), lactonase (LAC), and phenylacetate (ARE), as adapted from a
previous description [24]. Hydrolysis rate was followed in duplicate using a continuously
recording spectrophotometer (TECAN, Männedorf, Switzerland, Infinite M200).
In addition, the genotypic frequencies of PON1 L55M and Q192R were determined
by an allelic discrimination assay using real-time PCR using TaqMan fluorogenic probes
as described in [25], on saliva samples (FTA cards). Biological parameters related to
paraoxonase activities were also calculated such as individual enzyme activities/HDL ratio
and enzyme activities/apolipoprotein A1 ratio as previously described [22,26].

2.4. Statistical Considerations

Qualitative factors are described by means of the frequency of their respective modali-
ties and compared using Pearson’s Chi-square test (or Fisher’s test). Continuous factors are
described by means of their median (IQR) and compared using the Mann–Whitney test (or
Kruskal–Wallis test if more than 2 groups).
Invasive disease-free survival (iDFS) was defined as the time from the date of inclusion
in the study to the date the event occurred first (as defined in the DATECAN guidelines) or
censored at the last event-free date; iDFS was calculated and plotted using Kaplan–Meier
curves. Survival curves were compared using the log-rank test. Overall survival (OS) was
defined as the time from the date of inclusion to the date of death.
The median of follow-up was calculated using the inverse Kaplan–Meier method.
Analyses were performed using StataSE 17.0 software (StataCorp, College Station, TX, USA).
The tests were performed in two-tailed formulation and the significance limit was set
at 5%. Multivariate analyses were performed by including MS status, age, and Dietary
Inflammatory Index with survival parameters.

3. Results
3.1. Description of the Study Cohort and Metabolic Syndrome
The study cohort included n = 73 patients, and the clinico-biological parameters are
synthesized in Table 1 (one missing datum). The prevalence of MS in the whole study
population was 22/72 (30.5%) according to the NCEP definition.
As expected, SM+ patients were significantly older, mainly with menopausal status
with a lower performance status. In the same way, the subtype of breast cancer differed
according to the SM status.
We explored the interaction between metabolic syndrome and survival parameters.
As shown in Figure 2, overall survival (OS) was significantly longer in women without
metabolic syndrome (MS–) with HR 4.7 [1.11–19.92], p = 0.036.
 population was 22/72 (30.5%) according to the NCEP definition.
As expected, SM+ patients were significantly older, mainly with menopausa
with a lower performance status. In the same way, the subtype of breast cancer d
according to the SM status.

Nutrients 2024, 16, 3579 Table 1. Clinico-biological parameters of the studied population associated 5with
of 13validated
questionnaires.
SM+ (n = 22) SM− (n = 50) p-Value
Table 1.AgeClinico-biological
(years) * parameters of the 65
studied
(54–75) population associated
52 (44–63) with validated 0.006
dietary BMI
questionnaires.
(kg m ) *
−2 28.5 (25.7–30.9) 22.5 (20.6–24.9) <0.001
Menopausal status ** 18 (81.8%) 23 (46%) 0.005
Performance status = 0 SM+ (n = 22) 17 (77.3%)
SM− (n = 50) 50 (100%) p-Value 0.002
Type of cancer **
Age (years) * 65 (54–75) 52 (44–63) 0.006
Invasive
− 2 carcinoma of no special type (ductal) 13 (59.1%) 41 (82.0%)
BMI (kg m ) * 28.5 (25.7–30.9) 22.5 (20.6–24.9) <0.001 0.03
Invasive lobular carcinoma 9 (40.9%) 7 (14.0%)
Menopausal status ** 18 (81.8%) 23 (46%) 0.005
Other 0 (0%) 2 (4.0%)
Performance status = 0 17 (77.3%) 50 (100%) 0.002
Overexpression of estrogen receptor 22 (100%) 50 (100%)
Type of cancer ** HER2+ 0% 0%
Invasive carcinoma of no special Circulating
type (ductal)
lipids (mmol/L) 13 (59.1%) 41 (82.0%)
0.03
Invasive lobular carcinoma Plasma cholesterol 9 (40.9%) 7 (14.0%)
5.42 (4.74–5.94) 5.68 (4.94–6.67) 0.144
Other Plasma triglycerides 0 (0%) 2 (4.0%)
1.07 (0.74–1.59) 0.94 (0.72–1.30) 0.309
Overexpression of estrogen receptor HDL cholesterol 22 (100%) 1.26 (1.15–1.51)
50 (100%) 1.81 (1.58–2.03) <0.001
HER2+ LDL cholesterol 0% 3.26 (2.73–3.86)0% 3.42 (2.91–4.21) 0.303

Circulating lipids (mmol/L) * Median (25th–75th); ** frequency expressed as n (percentage); Mann–Whitney test; n = 7
Plasma cholesterol missing 5.42
datum.
(4.74–5.94) 5.68 (4.94–6.67) 0.144
Plasma triglycerides 1.07 (0.74–1.59) 0.94 (0.72–1.30) 0.309
HDL cholesterol We1.26
explored the interaction between
(1.15–1.51) metabolic syndrome
1.81 (1.58–2.03) and survival para
<0.001
LDL cholesterol As shown in Figure 2, overall survival (OS) was significantly longer in women w
3.26 (2.73–3.86) 3.42 (2.91–4.21) 0.303
metabolic
* Median (25th–75th); syndrome
** frequency expressed as(MS–) with HR
n (percentage); 4.7 [1.11–19.92],
Mann–Whitney test; n =p72;
= n0.036.
= 1 missing datum.

Figure 2. Overall survival with and without the presence of metabolic syndrome (MS+ vs. MS−); n = 68.
Figure 2. Overall survival with and without the presence of metabolic syndrome (MS+ vs. MS−)
In the same way (Figure 3), iDFS was significantly longer in women with MS– with
HR 3.58 [1.23–10.44], p = 0.019, although the metabolic syndrome status did not appear to
have influence on the relapse-free survival (HR = 2.14 [0.57–8.08], p = 0.262).
However, on multivariate analysis including age, MS still remained significantly
associated with iDFS but not with OS.

3.2. Dietary Habits and Dietary Inflammatory Index

In patients with validated dietary questionnaires (n = 73), the median [25th–75th]
daily energy intake and macronutrients carbohydrate, protein, and lipids were 2042 kcal/d
[1550–2910], 220 g/d [188–254] (43.4% of energy intake or EI), 85.9 g/d [76.9–100] (16.7%
EI), and 82.9 g/d [72.3–92] (36.7% EI), respectively. More specifically for lipids, the daily
intakes of total FA, saturated FAs, MUFAs, and PUFAs ω3 and w6 daily amounts were
Nutrients 2024, 16, x FOR PEER REVIEW 6 of 13

In the same way (Figure 3), iDFS was significantly longer in women with MS– with
Nutrients 2024, 16, 3579 6 of 13
HR 3.58 [1.23–10.44], p = 0.019, although the metabolic syndrome status did not appear to
have influence on the relapse-free survival (HR = 2.14 [0.57–8.08], p = 0.262).
However, on multivariate analysis including age, MS still remained significantly
61.4 g/d [51.1–76.0],
associated 30.3not
with iDFS but g/d [20.8–37.4],
with OS. 22.7 g/d [17.5–27.4], 8.8 g/d [6.6–13.1] g/d,
1.1 g/d [0.9–1.9], and 7.2 g/d [5.2–9.9], respectively.

Figure 3. iDFS with and without the presence of metabolic syndrome (MS+ vs. MS−); n = 68.
Figure 3. iDFS with and without the presence of metabolic syndrome (MS+ vs. MS−); n = 68.
For each validated questionnaire, the Dietary Inflammatory Index or DII was cal-
3.2. Dietary
culated by Habits and Dietary
including 27 items Inflammatory
as described Index
above. The median value of the DII was
−0.43In[25th–75th: −1.61,
patients with 0.26]. The
validated negative
dietary value of the (n
questionnaires DII=score suggests
73), the median that[25th–75th]
the dietary
habitsenergy
daily in our intake
cohortand
tendmacronutrients
to be anti-inflammatory. Noneprotein,
carbohydrate, of the survival
and lipidsparameters,
were 2042such as
kcal/d
overall survival, relapse-free survival, and invasive disease-free survival,
[1550–2910], 220 g/d [188–254] (43.4% of energy intake or EI), 85.9 g/d [76.9–100] (16.7% were associated
withand
EI), DII82.9
scoreg/d
with HR [95%
[72.3–92] CI]: 1.43
(36.7% EI), [0.92–2.23] (p =More
respectively. 0.11),specifically
0.996 [0.69–1.43] (p = 0.98),
for lipids, and
the daily
1.11 [0.82–1.50] (p = 0.5), respectively. Moreover, the DII score was
intakes of total FA, saturated FAs, MUFAs, and PUFAs ω3 and w6 daily amounts were not associated with any
other
61.4 biological
g/d parameters
[51.1–76.0], 30.3 g/d related to paraoxonase
[20.8–37.4], activities.8.8 g/d [6.6–13.1] g/d, 1.1 g/d
22.7 g/d [17.5–27.4],
[0.9–1.9], and 7.2 g/d [5.2–9.9], respectively.
3.3. LXR-Regulated Genes of Cholesterol Trafficking, Lipidic Dietary Habits, and Survival Parameters
For each validated questionnaire, the Dietary Inflammatory Index or DII was
The expression
calculated of different
by including 27 itemsLXR-regulated
as describedgenes
above. of The
cholesterol
mediantrafficking
value of intheperipheral
DII was
leukocytes was evaluated at baseline and at week 5 (Table 2).
−0.43 [25th–75th: −1.61, 0.26]. The negative value of the DII score suggests that the dietary
habits in our cohort tend to be anti-inflammatory. None of the survival parameters, such
Table 2. LXR-regulated genes of cholesterol trafficking expression of peripheral leucocytes at baseline
as overall survival, relapse-free survival, and invasive disease-free survival, were
and week 5 (arbitrary units = AU).
associated with DII score with HR [95% CI]: 1.43 [0.92–2.23] (p = 0.11), 0.996 [0.69–1.43] (p
= 0.98), and
Genes1.11 [0.82–1.50] (p = 0.5), respectively. AU Moreover,
(n = 50) the DII score was not
associated with any other biologicalBaseline parameters related to
Week 5 paraoxonase activities.
p-Value
ABCG1 1.47 [1.06–1.85] 1.23 [0.94–1.70] 0.72
3.3. LXR-Regulated Genes of Cholesterol Trafficking, Lipidic Dietary Habits, and Survival
ABCA1
Parameters 1.40 [1.01–2.10] 1.40 [1.01–2.10] 0.61

The PON2 0.58 [0.50–0.73]

expression of different LXR-regulated 0.65genes
[0.52–0.70] 0.47
of cholesterol trafficking in
peripheral leukocytes was evaluated
LXRb at baseline and
1.46 [0.95–2.34] 1.49at week 5 (Table 2).
[1.01–2.30] 0.98
The
Results expression
expressed of[25th–75th];
as median LXR-regulated genes
missing data n = 23ofinsufficient
cholesterol
RNA. trafficking in peripheral
leukocytes remained stable after tamoxifen treatment, as no difference was observed
betweenThebaseline andofweek
expression 5.
LXR-regulated genes of cholesterol trafficking in peripheral leuko-
The link between the expressions of
cytes remained stable after tamoxifen treatment, these genes at difference
as no baseline andwasdietary habits,
observed more
between
specifically
baseline and lipids,
weekwas5. explored, in addition to the relation with the survival parameters.
The link between the expressions of these genes at baseline and dietary habits, more
specifically lipids, was explored, in addition to the relation with the survival parame-
ters. The expression of ABCG1 at baseline, an ATP-binding cassette transporter involved
 kocytes were associated with overall survival with HR [95%CI]: 1.38 [0.56–3.39], p = 0.48;
0.53 [0.02–19.06], p = 0.73; and 1.28 [0.65–2.53], p = 0.47, respectively. Moreover, no link
was observed with invasive disease-free survival

Table 2. LXR-regulated genes of cholesterol trafficking expression of peripheral leucocytes at base-

Nutrients 2024, 16, 3579
line and week 5 (arbitrary units = AU). 7 of 13

Genes AU (n = 50)
Baseline Week 5 p-Value
in cholesterol and phospholipid trafficking, was significantly associated with invasive
ABCG1disease-free survival1.47 [1.06–1.85]
(1.38-[1.1–1.9], p = 1.23 [0.94–1.70]
0.048) and tended to be0.72 significant with overall
ABCA1survival (1.44-[1.0–2.1],
1.40 [1.01–2.10] 1.40 [1.01–2.10]
p = 0.055). In addition, ABCA1, PON2, and 0.61 LXRb expression in
PON2leukocytes were0.58 [0.50–0.73]
associated 0.65 [0.52–0.70]
with overall survival with HR [95%CI]:0.47 1.38 [0.56–3.39], p = 0.48;
LXRb0.53 [0.02–19.06],1.46 p =[0.95–2.34]
0.73; and 1.28 [0.65–2.53], p = 0.47, respectively.
1.49 [1.01–2.30] Moreover, no link was
0.98
observed with invasive disease-free survival.
Results expressed as median [25th–75th]; missing data n = 23 insufficient RNA.
As described in Figure 4A, high ABCG1 expression in peripheral leukocytes is corre-
As describedlated with a4A,
in Figure higher ratio of dietary
high ABCG1 PUFA
expression ω6/ω3 (Spearman
in peripheral correlated= 0.412, p = 0.01)
leukocytesr iscorrelation
and
with a higher ratio % of ω3
of dietary expressed
PUFA as % total rdietary
ω6/ω3 (Spearman lipids
correlation (B) (Spearman
= 0.412, p = 0.01) andr correlation
% of = −0.391,
ω3 expressed as %p =total
0.024).
dietary lipids (B) (Spearman r correlation = −0.391, p = 0.024).

Figure 4. Relationship between ABCG1 leucocyte expression and the ratio of dietary ω6/ω3 (A) and
Figure 4. Relationship between ABCG1 leucocyte expression and the ratio of dietary ω6/ω3 (A) and
omega 3, expressed as % of total dietary lipids (B).
omega 3, expressed as % of total dietary lipids (B).
3.4. Paraoxonase 3.4. Paraoxonase
3.4.1. Link Between Enzyme
3.4.1. Activities
Link Between and Paraoxonase
Enzyme Genotypes
Activities and Paraoxonase Genotypes
The three enzymatic activities
The three of paraoxonase
enzymatic ARE,
activities of LAC, andARE,
paraoxonase PON LAC,
quantified at quantified at
and PON
baseline on the cohort studied were 21.6 mmol/L/min [17.1–31.9], 0.174 µmol/L/min µmol/L/min
baseline on the cohort studied were 21.6 mmol/L/min [17.1–31.9], 0.174
[0.155–0.192],
[0.155–0.192], and and 114
114 µmol/L/min (64–201), [64–201],
respectively.
µmol/L/min respectively.
As shown As3,shown
in Table in Table 3, the genetic
the genetic
polymorphism
polymorphism L155M did not L155M
seem todid not seem
impact anytoofimpact any enzyme
the three of the three enzyme
activities activities PON, ARE,
PON,
ARE, or LAC (n or LAC (n = 69).
= 69).
Table 3. Paraoxonase activities according to the PON L155M gene polymorphism.
Table 3. Paraoxonase activities according to the PON L155M gene polymorphism.
vities Activities
L/L (n = 30) L/L
M/L(n(n==30)
34) M/L
M/M(n (n
= 34)
= 5) M/M (n = 5)
P global LLPvs.
Global
ML PLL
MLvs.
vs.ML
MM P ML vs.MM
LL vs. MM LL vs. MM
RE 20.5 23.9 50.9
ARE 20.5 23.9 50.9
0.18 ns ns ns
L/min [17.4–25.9] [15.9–38.2] [18.2–59.0] 0.18 ns ns ns
mmol/L/min [17.4–25.9] [15.9–38.2] [18.2–59.0]
AC 0.177 0.174 0.171
0.71 ns ns ns
L/min LAC
[0.16–0.187] 0.177
[0.15–0.20] 0.174
[0.13–0.177] 0.171
0.71 ns ns ns
ON µmol/L/min
109 [0.16–0.187]
123.5 [0.15–0.20]
81 [0.13–0.177]
0.34 ns ns ns
L/min [64–165]
PON [71–209]
109 [51–112]
123.5 81
µmol/L/minResults expressed as median
[64–165] [71–209][25th–75th], n = 69 patients;0.34
[51–112] missing data nns
= 4. ns ns

Results expressed as median [25th–75th], n = 69 patients; missing data n = 4.

Conversely, ARE, PON, and LAC activities differed according to the Q192R polymor-
phism (Table 4). Indeed, the presence of the allele R seemed to decrease the ARE activity,
whereas increased LAC and PON activities were observed (n = 68).

3.4.2. Link Between Paraoxonase Activities and Lipid Dietary Habits

The ARE activity is positively correlated with the daily dietary PUFA ratio ω6/ω3
with R = 0.265 (p = 0.027). The daily amount of dietary PUFA ω6 is also positively associated
with LAC activity and the ARE activity/apolipoprotein A1 ratio with R = 0.24 (p = 0.04) and
Nutrients 2024, 16, 3579 8 of 13

R = 0.278 (p = 0.036), respectively. No other correlation was observed between paraoxonase

activities expressed as HDL or the apolipoprotein ratio.

Table 4. Paraoxonase activities according to PON Q192R gene polymorphism.

Activities Q/Q R/Q R/R P

(n = 34) (n = 25) (n = 9) P Global QQ vs. RQ RQ vs. RR QQ vs. RR
ARE 27.9 19.3 18.2
0.036 0.016 1 0.11
mmol/L/min [18.5–38.0] [14.8–23.9] [14.8–31]
LAC 0.172 0.174 0.187
0.032 0.27 0.081 0.01
µmol/L/min [0.143–0.18] [0.16–0.20] [0.18–0.21]
PON 69 168 242
<0.0001 <0.0001 0.61 0.04
µmol/L/min [52.2–99.5] [120–218] [69–285]
Results expressed as median [25th–75th], n = 68 patients; missing data n = 5.

3.4.3. Link Between Paraoxonase Activities and Survival Parameters

Paraoxonase activities, whatever their expression—global activities, the ratio on HDL,
or the ratio on apolipoprotein A1—were not associated with overall survival in breast
cancer patients. However, our results suggest that a higher LAC/HDL ratio was associated
with an increased risk of recurrence (HR = 2.54 [1.25–5.19], p = 0.01). In addition, the
PON/apoA1 ratio was inversely associated with iDFS (HR = 0.34 [0.12–0.98], p = 0.04).

4. Discussion
The aim was to explore the link between survival metabolic syndrome, lipid biomark-
ers, and dietary habits with survival parameters in a cohort of women with early-stage
hormone-dependent breast cancer (BC).
The molecular subtype of breast cancer is luminal A, which is the main type of early-
stage BC. The clinical and anthropometric characteristics are in agreement with the usually
described data.
Among the different objectives of this work, we aimed to determine the frequency
of metabolic syndrome (MS) in the studied population and explore its link with survival
parameters. A cluster of metabolic risk factors including abdominal obesity, hypertension,
dyslipidemia, insulin resistance, and low HDL-C plasma concentration defines metabolic
syndrome [15]. For many decades, this syndrome has been associated with an increased
cardiovascular risk [27]. This is mainly due to the poor quality of nutritional habits with
high saturated fatty acids and carbohydrates [28,29]. The quality of dietary fatty acids
must be taken into account as a Mediterranean diet regimen rich in olive oil intake clearly
improved MS criteria [29]. The prevalence of MS reaches epidemic proportions in Western
countries and varies according to sociodemographic status, age, and gender. The prevalence
of MS in our cohort (30.5%) is consistent with that described in epidemiological studies such
as MONICA related to the age of patients (26% for 55–65-year-olds [30]) and in women with
breast cancer [31], and will probably increase in the next decade in parallel with obesity.
The link between MS and cancer has been explored with a central role in insulin resistance
and insulin-like GF1, but also secreted adipokines and free fatty acids [32].
Therefore, MS is strongly suggested to increase the risk of several cancer localizations
such as breast cancer as described in a meta-analysis [33] in postmenopausal women
(1.56, p = 0.017).
Our results show a link between metabolic syndrome and the decrease in overall
survival, and also iDFS. These data are in complete agreement with those previously
published [34–37], for example, in the large epidemiologic study WHI, which concluded
that postmenopausal women with 3–4 MS components had a higher risk of death from
breast cancer [36] (compared to none).
Nutrients 2024, 16, 3579 9 of 13

Recent work in early ER+ cancer [38] even suggests that the relative risk of endocrine-
resistant tumor was 1.4-fold greater for patients with MS (p = 0.0197).
The dietary habits of the study population were explored by self-assessment ques-
tionnaires. Different strategies could be used to evaluate dietary patterns of a population,
such as a food frequency questionnaire, a food diary or food record with data collected for
at least 2 days, or two or more 24 h recalls. Nevertheless, a standardized approach could
be helpful [39].
The macronutrients and lipid consumption of our cohort are in the same range as
those described in a large French nutritional epidemiological study INCA3 [40] for the
main parameters (energy, lipids, carbohydrates, total protein, and % energy amount). It
seems that our patients’ dietary habits are closer to the French dietary recommendations
with, for example, a daily energy intake around 2072 kcal/d vs. 1787 kcal/d for women
age-matched to INCA3 for a recommendation of 1800–2200 kcal/d. Our patients also have
the same dietary intakes of total FA and PUFAs ω6 and ω3 compared to INCA3. However,
our approach to evaluate dietary intakes in our cohort could be improved by using a more
complete nutrient database than Ciqual 2020, such as EPIC nutrient database [41].
The impact of food intake on inflammation could be determined by the dietary inflam-
matory score [8]. The dietary inflammatory score is described as a new tool that enables
researchers to describe the pattern of people’s diet to determine whether their food intake
is more anti- or pro-inflammatory. The interest in this score has risen for two decades and
originally included 45 nutrients to characterize the inflammatory profile of the diet [6].
The link between breast cancer risk and DII has been largely suggested in Swedish,
Chinese, and Iranian studies and meta-analyses [20,42–44]. Few studies like ours have
investigated the link between DII score and breast cancer survival parameters, and like
Zuchetto et al. (2017) [45], our findings did not suggest an association between the inflam-
matory potential of the diet, measured by the DII, and breast cancer survival parameters, in
contrast to [46] where a higher risk of death from BC was associated with the consumption
of a more pro-inflammatory diet at baseline (HRQ5vsQ1 , 1.33; 95% CI, 1.01–1.76; Ptrend = 0.03).
Our results could probably be explained by the small number of studied questionnaires but
also by the inability to include different components (like in the original DII calculation),
such as ginger, turmeric, garlic, oregano, pepper, rosemary, eugenol, saffron, flavan-3-ol,
flavones, flavonols, flavonones, and anthocyanidins. Experiments have been undertaken to
validate our DII as described in [47].
To explore the impact of the cell lipidic metabolic actors on breast cancer survival
parameters, LXR-regulated genes of cholesterol trafficking expressions in peripheral leuko-
cytes were evaluated, at baseline.
The link between the peripheral expression of these genes and survival parameters has
not been extensively studied. In the present study, ABCG1 (involved in cholesterol efflux
from the cell) expression at baseline was significantly associated with iDFS and tended to
be associated with overall survival.
On the other hand, in a previous work, we had shown that tumor ABCG1 was related
to the disease severity with a lower expression in the highest SBR-grade tumor (pejorative
situation) [23]. The tumor expression levels of LXR-regulated genes of cholesterol trafficking
also differ according to the subtype of metastatic breast cancer as previously suggested [48].
The expression of liver X receptor (LXR)-regulated genes of cholesterol trafficking
such as ABCG1 expression in cholesterol influx and efflux mediators is also influenced by
dietary intake. Our data suggest that ABCG1 expression in PBMC is associated with a high
dietary PUFA ratio ω6/ω3, which is not really in agreement with the literature. According
to the literature, the expressions of ABCG1 and ABCA1 on PBMC are increased with high
intakes of SFA rather than PUFA [48].
However, the significance of our results is limited by the small number of patients and
therefore needs to be confirmed by a larger-cohort approach.
Previously extensively studied from a cardiovascular point of view, paraoxonase 1 is
carried in the plasma by high-density lipoproteins (HDLs) and protects low-density lipopro-
Nutrients 2024, 16, 3579 10 of 13

teins from oxidation (LDL). It is well accepted that PON activity is lower in cancer patients
than in controls and, in a previous work, we identified paraoxonase as a potential marker of
survival in patients with breast cancer recurrence [49]. The enzymatic activities quantified
in our cohort are consistent with those previously described by our team. However, it
seems difficult to compare our results with other published data as many different methods
of enzymatic measurement have been described [50,51]. As it has been described, PON1
levels depend on genetic polymorphisms [52]. In our cohort, the frequencies of the poly-
morphisms PON1192 and PON155 are in agreement with those described in the Caucasian
population (recent review in [53]).
PON1 activities are modified by dietary intake. The consumption of polyphenols-
enriched diets may increase PON1 activity. The Mediterranean diet has also been shown to
have a beneficial effect on PON1 activity. Extra virgin olive oil (ω9) seems to increase PON1
activity through the oleic acid enrichment of phospholipids present in HDL. This oil favored
PON1 activity and increased hepatic PON1 mRNA and protein expression. These effects
could be attributed to minor components present in this oil (terpenes, phytosterols). The
high consumption of fruits and vegetables in the Mediterranean diet could also contribute
to the modulation of paraoxonase activities [54].
In our previous study, paraoxonase 1 was identified as a marker of short-term death
with cancer recurrence [23]. This new study confirms the interest of the early quantification
of paraoxonase activity as we have shown the significant inverse association between
PON/apoA1 and iDFS, but also a positive association between LAC/HDL and RFS.
These unexpected data need to be confirmed in a large breast cancer cohort.

5. Conclusions
MS is associated with reduced survival parameters in early-stage breast cancer. The
peripheral leukocytes expression of ABCG1 involved in cholesterol trafficking is related to
survival parameters. Despite the smaller sample size of the present study, our results are in
agreement with previously published data on the impact of genetic and non-genetic factors
(diet) to modulate paraoxonase activities. The impact of PON1 on iDFS in women with
early-stage breast cancer is described for the first time. A mechanistic approach and larger
clinical studies are needed to confirm these data.
This study highlights the relationship between early-stage breast cancer survival
parameters, metabolic syndrome, and some parameters related to lipid metabolism.

Author Contributions: Methodology, C.B.-D., L.C. and J.-M.B.; Formal analysis, L.C. and C.B.; Inves-
tigation, C.B.-D., J.-S.F. and M.C.; Resources, C.B.-D., C.B., E.R. and J.-M.B.; Writing—original draft,
C.B.-D. and C.B.; Writing—review & editing, C.B.-D. and J.-M.B.; Visualization, C.B.-D.; Supervision,
C.B.-D. and J.-M.B.; Project administration, J.-M.B.; Funding acquisition, C.B.-D. and M.C. All authors
have read and agreed to the published version of the manuscript.
Funding: PHRC 2008, Ministère de la Santé et des Solidarités France.
Institutional Review Board Statement: The trial was conducted following the Declaration of Helsinki,
Good Clinical Practice Guides (CPMP/ICH/135/95) and the current French legislation regard-
ing clinical trials (EUDRACT 2008-007652-10). The protocol was approved by CPP Centre Ouest,
Tours, France (Approval date: 6 April 2009).
Informed Consent Statement: Informed consent was obtained from all subjects involved in
the study.
Data Availability Statement: The original contributions presented in the study are included in the
article, further inquiries can be directed to the corresponding author.
Conflicts of Interest: The authors declare no conflict of interest.
Nutrients 2024, 16, 3579 11 of 13

References
1. Breast Cancer Statistics|World Cancer Research Fund International. WCRF International. Available online: https://www.wcrf.
org/cancer-trends/breast-cancer-statistics/ (accessed on 24 July 2024).
2. Toledo, E.; Salas-Salvadó, J.; Donat-Vargas, C.; Buil-Cosiales, P.; Estruch, R.; Ros, E.; Corella, D.; Fitó, M.; Hu, F.B.; Arós, F.; et al.
Mediterranean Diet and Invasive Breast Cancer Risk Among Women at High Cardiovascular Risk in the PREDIMED Trial:
A Randomized Clinical Trial. JAMA Intern. Med. 2015, 175, 1752–1760. [CrossRef] [PubMed]
3. González-Palacios Torres, C.; Barrios-Rodríguez, R.; Muñoz-Bravo, C.; Toledo, E.; Dierssen, T.; Jiménez-Moleón, J.J. Mediterranean
Diet and Risk of Breast Cancer: An Umbrella Review. Clin. Nutr. 2023, 42, 600–608. [CrossRef]
4. Huang, P.L. A Comprehensive Definition for Metabolic Syndrome. Dis. Models Mech. 2009, 2, 231–237. [CrossRef] [PubMed]
5. D’Angelo, S.; Motti, M.L.; Meccariello, R. ω-3 and ω-6 Polyunsaturated Fatty Acids, Obesity and Cancer. Nutrients 2020, 12, 2751.
[CrossRef]
6. Shivappa, N.; Steck, S.E.; Hurley, T.G.; Hussey, J.R.; Hébert, J.R. Designing and Developing a Literature-Derived, Population-Based
Dietary Inflammatory Index. Public Health Nutr. 2014, 17, 1689–1696. [CrossRef]
7. Guo, R.; Chen, Y.; Borgard, H.; Jijiwa, M.; Nasu, M.; He, M.; Deng, Y. The Function and Mechanism of Lipid Molecules and Their
Roles in The Diagnosis and Prognosis of Breast Cancer. Molecules 2020, 25, 4864. [CrossRef] [PubMed]
8. Lund, E.G.; Peterson, L.B.; Adams, A.D.; Lam, M.-H.N.; Burton, C.A.; Chin, J.; Guo, Q.; Huang, S.; Latham, M.; Lopez, J.C.; et al.
Different Roles of Liver X Receptor α and β in Lipid Metabolism: Effects of an α-Selective and a Dual Agonist in Mice Deficient
in Each Subtype. Biochem. Pharmacol. 2006, 71, 453–463. [CrossRef]
9. Nazih, H.; Bard, J.M. Cholesterol, Oxysterols and LXRs in Breast Cancer Pathophysiology. Int. J. Mol. Sci. 2020, 21, 1356.
[CrossRef]
10. Bacchetti, T.; Ferretti, G.; Sahebkar, A. The Role of Paraoxonase in Cancer. Semin. Cancer Biol. 2019, 56, 72–86. [CrossRef]
11. Mackness, M.; Mackness, B. Human Paraoxonase-1 (PON1): Gene Structure and Expression, Promiscuous Activities and Multiple
Physiological Roles. Gene 2015, 567, 12–21. [CrossRef]
12. Ferretti, G.; Bacchetti, T. Effect of Dietary Lipids on Paraoxonase-1 Activity and Gene Expression. Nutr. Metab. Cardiovasc. Dis.
2012, 22, 88–94. [CrossRef] [PubMed]
13. Hussein, Y.M.; Gharib, A.F.; Etewa, R.L.; ElSawy, W.H. Association of L55M and Q192R Polymorphisms in Paraoxonase 1 (PON1)
Gene with Breast Cancer Risk and Their Clinical Significance. Mol. Cell Biochem. 2011, 351, 117–123. [CrossRef] [PubMed]
14. Farmohammadi, A.; Momeni, A.; Bahmani, B.; Ghorbani, H.; Ramzanpour, R. Association of PON1-L55M Genetic Variation and
Breast Cancer Risk: A Case-Control Trial. Asian Pac. J. Cancer Prev. 2020, 21, 255–258. [CrossRef]
15. Eckel, R.H.; Grundy, S.M.; Zimmet, P.Z. The Metabolic Syndrome. Lancet 2005, 365, 1415–1428. [CrossRef] [PubMed]
16. Bard, J.; Drouet, L.; Lairon, D.; Cazaubiel, M.; Marmonier, C.; Ninio, E.; Bal Dit Sollier, C.; Martin, J.; Boyer, C.; Bobin-Dubigeon, C.
Effect of Milk Fat on LDL Cholesterol and Other Cardiovascular Risk Markers in Healthy Humans: The INNOVALAIT Project.
Eur. J. Clin. Nutr. 2020, 74, 285–296. [CrossRef] [PubMed]
17. Ciqual Table de Composition Nutritionnelle Des Aliments. Available online: https://ciqual.anses.fr/ (accessed on 27 March 2023).
18. Black, A.E. The Sensitivity and Specificity of the Goldberg Cut-off for EI:BMR for Identifying Diet Reports of Poor Validity. Eur. J.
Clin. Nutr. 2000, 54, 395–404. [CrossRef]
19. Phillips, C.M.; Shivappa, N.; Hébert, J.R.; Perry, I.J. Dietary Inflammatory Index and Biomarkers of Lipoprotein Metabolism,
Inflammation and Glucose Homeostasis in Adults. Nutrients 2018, 10, 1033. [CrossRef]
20. Phillips, C.M.; Chen, L.-W.; Heude, B.; Bernard, J.Y.; Harvey, N.C.; Duijts, L.; Mensink-Bout, S.M.; Polanska, K.; Mancano, G.;
Suderman, M.; et al. Dietary Inflammatory Index and Non-Communicable Disease Risk: A Narrative Review. Nutrients 2019,
11, 1873. [CrossRef]
21. Kranz, S.; Hasan, F.; Kennedy, E.; Zoellner, J.; Guertin, K.A.; Shivappa, N.; Hébert, J.R.; Anderson, R.; Cohn, W. Diet Quality and
Dietary Inflammatory Index Score among Women’s Cancer Survivors. Int. J. Environ. Res. Public Health 2022, 19, 1916. [CrossRef]
22. Bobin-Dubigeon, C.; Nazih, H.; Croyal, M.; Bard, J.-M. Link between Omega 3 Fatty Acids Carried by Lipoproteins and Breast
Cancer Severity. Nutrients 2022, 14, 2461. [CrossRef]
23. Bobin-Dubigeon, C.; Chauvin, A.; Brillaud-Meflah, V.; Boiffard, F.; Joalland, M.; Bard, J. Liver X Receptor (LXR)-Regulated Genes
of Cholesterol Trafficking and Breast Cancer Severity. Anticancer Res. 2017, 37, 5495–5498. [CrossRef] [PubMed]
24. Bobin-Dubigeon, C.; Lefrançois, A.; Classe, J.; Joalland, M.; Bard, J. Paired Measurement of Serum Amyloid A (SAA) and
Paraoxonase 1 (PON1) as Useful Markers in Breast Cancer Recurrence. Clin. Biochem. 2015, 48, 1181–1183. [CrossRef] [PubMed]
25. Alegría-Torres, J.A.; García-Domínguez, M.L.; Cruz, M.; Aradillas-García, C. Q192R Polymorphism of Paraoxonase 1 Gene
Associated with Insulin Resistance in Mexican Children. Arch. Med. Res. 2015, 46, 78–83. [CrossRef]
26. Bobin-Dubigeon, C.; Nazih, H.; Blanchard, V.; Croyal, M.; Bard, J.-M. Circulating HDL and Non-HDL Associated Apolipoproteins
and Breast Cancer Severity. J. Clin. Med. 2022, 11, 1345. [CrossRef]
27. Samson, S.L.; Garber, A.J. Metabolic Syndrome. Endocrinol. Metab. Clin. N. Am. 2014, 43, 1–23. [CrossRef]
28. Ambroselli, D.; Masciulli, F.; Romano, E.; Catanzaro, G.; Besharat, Z.M.; Massari, M.C.; Ferretti, E.; Migliaccio, S.; Izzo, L.;
Ritieni, A.; et al. New Advances in Metabolic Syndrome, from Prevention to Treatment: The Role of Diet and Food. Nutrients
2023, 15, 640. [CrossRef]
Nutrients 2024, 16, 3579 12 of 13

29. Castro-Barquero, S.; Ruiz-León, A.M.; Sierra-Pérez, M.; Estruch, R.; Casas, R. Dietary Strategies for Metabolic Syndrome:
A Comprehensive Review. Nutrients 2020, 12, 2983. [CrossRef]
30. Saklayen, M.G. The Global Epidemic of the Metabolic Syndrome. Curr. Hypertens. Rep. 2018, 20, 12. [CrossRef] [PubMed]
31. Zhou, Z.; Zhang, Y.; Li, Y.; Jiang, C.; Wu, Y.; Shang, L.; Huang, Y.; Cheng, S. Metabolic Syndrome Is a Risk Factor for Breast Cancer
Patients Receiving Neoadjuvant Chemotherapy: A Case-Control Study. Front. Oncol. 2023, 12, 1080054. [CrossRef]
32. Uzunlulu, M.; Caklili, O.T.; Oguz, A. Association between Metabolic Syndrome and Cancer. ANM 2016, 68, 173–179. [CrossRef]
33. Esposito, K.; Chiodini, P.; Colao, A.; Lenzi, A.; Giugliano, D. Metabolic Syndrome and Risk of Cancer: A Systematic Review and
Meta-Analysis. Diabetes Care 2012, 35, 2402–2411. [CrossRef] [PubMed]
34. Bjørge, T.; Lukanova, A.; Jonsson, H.; Tretli, S.; Ulmer, H.; Manjer, J.; Stocks, T.; Selmer, R.; Nagel, G.; Almquist, M.; et al. Metabolic
Syndrome and Breast Cancer in the Me-Can (Metabolic Syndrome and Cancer) Project. Cancer Epidemiol. Biomark. Prev. 2010,
19, 1737–1745. [CrossRef] [PubMed]
35. Gathirua-Mwangi, W.G.; Song, Y.; Monahan, P.; Champion, V.L.; Zollinger, T. Associations of Metabolic Syndrome and C-Reactive
Protein with Mortality from Total Cancer, Obesity-Linked Cancers and Breast Cancer among Women in NHANES III. Int. J.
Cancer 2018, 143, 535–542. [CrossRef]
36. Pan, K.; Aragaki, A.K.; Neuhouser, M.L.; Simon, M.S.; Luo, J.; Caan, B.; Snetselaar, L.; Mortimer, J.E.; Manson, J.E.;
Kroenke, C.; et al. Low-Fat Dietary Pattern and Breast Cancer Mortality by Metabolic Syndrome Components: A Secondary
Analysis of the Women’s Health Initiative (WHI) Randomised Trial. Br. J. Cancer 2021, 125, 372–379. [CrossRef]
37. Chlebowski, R.T.; Aragaki, A.K.; Pan, K.; Simon, M.S.; Neuhouser, M.L.; Haque, R.; Rohan, T.E.; Wactawski-Wende, J.;
Orchard, T.S.; Mortimer, J.E.; et al. Breast Cancer Incidence and Mortality by Metabolic Syndrome and Obesity: The Women’s
Health Initiative. Cancer 2024, 130, 3147–3156. [CrossRef]
38. Bergman, R.; Berko, Y.A.; Sanchez, V.; Sanders, M.E.; Gonzalez-Ericsson, P.I.; Arteaga, C.L.; Rexer, B.N. Obesity and Metabolic
Syndrome Are Associated with Short-Term Endocrine Therapy Resistance in Early ER + Breast Cancer. Breast Cancer Res. Treat.
2023, 197, 307–317. [CrossRef] [PubMed]
39. Wingrove, K.; Lawrence, M.A.; McNaughton, S.A. A Systematic Review of the Methods Used to Assess and Report Dietary
Patterns. Front. Nutr. 2022, 9, 892351. [CrossRef]
40. Rapport d’Expertise Collective. Avis de l’ANSES. Etude Individuelle des Consommations Alimentaires 3 (INCA3) Juin 2017.
Available online: https://www.anses.fr/fr/content/avis-et-rapport-de-lanses-sur-lactualisation-de-la-base-de-donnees-des-
consommations (accessed on 24 July 2024).
41. Iguacel, I.; Perez-Cornago, A.; Schmidt, J.A.; Van Puyvelde, H.; Travis, R.; Casagrande, C.; Nicolas, G.; Riboli, E.;
Weiderpass, E.; Ardanaz, E.; et al. Evaluation of Protein and Amino Acid Intake Estimates from the EPIC Dietary Ques-
tionnaires and 24-h Dietary Recalls Using Different Food Composition Databases. Nutr. Metab. Cardiovasc. Dis. 2022,
32, 80–89. [CrossRef]
42. Shivappa, N.; Sandin, S.; Löf, M.; Hébert, J.R.; Adami, H.-O.; Weiderpass, E. Prospective Study of Dietary Inflammatory Index
and Risk of Breast Cancer in Swedish Women. Br. J. Cancer 2015, 113, 1099–1103. [CrossRef]
43. Huang, W.-Q.; Mo, X.-F.; Ye, Y.-B.; Shivappa, N.; Lin, F.-Y.; Huang, J.; Hébert, J.R.; Yan, B.; Zhang, C.-X. A Higher Dietary
Inflammatory Index Score Is Associated with a Higher Risk of Breast Cancer among Chinese Women: A Case-Control Study. Br. J.
Nutr. 2017, 117, 1358–1367. [CrossRef]
44. Fowler, M.E.; Akinyemiju, T.F. Meta-Analysis of the Association between Dietary Inflammatory Index (DII) and Cancer Outcomes.
Int. J. Cancer 2017, 141, 2215–2227. [CrossRef] [PubMed]
45. Zucchetto, A.; Serraino, D.; Shivappa, N.; Hébert, J.R.; Stocco, C.; Puppo, A.; Falcini, F.; Panato, C.; Dal Maso, L.; Polesel, J.
Dietary Inflammatory Index before Diagnosis and Survival in an Italian Cohort of Women with Breast Cancer. Br. J. Nutr. 2017,
117, 1456–1462. [CrossRef]
46. Tabung, F.K.; Steck, S.E.; Liese, A.D.; Zhang, J.; Ma, Y.; Caan, B.; Chlebowski, R.T.; Freudenheim, J.L.; Hou, L.;
Mossavar-Rahmani, Y.; et al. Association between Dietary Inflammatory Potential and Breast Cancer Incidence and
Death: Results from the Women’s Health Initiative. Br. J. Cancer 2016, 114, 1277–1285. [CrossRef]
47. Tabung, F.K.; Steck, S.E.; Zhang, J.; Ma, Y.; Liese, A.D.; Agalliu, I.; Hingle, M.; Hou, L.; Hurley, T.G.; Jiao, L.; et al.
Construct Validation of the Dietary Inflammatory Index among Postmenopausal Women. Ann. Epidemiol. 2015,
25, 398–405. [CrossRef]
48. Pan, H.; Zheng, Y.; Pan, Q.; Chen, H.; Chen, F.; Wu, J.; Di, D. Expression of LXR-β, ABCA1 and ABCG1 in Human Triple-Negative
Breast Cancer Tissues. Oncol. Rep. 2019, 42, 1869–1877. [CrossRef] [PubMed]
49. Bobin-Dubigeon, C.; Jaffré, I.; Joalland, M.; Classe, J.; Campone, M.; Hervé, M.; Bard, J. Paraoxonase 1 (PON1) as a Marker of
Short Term Death in Breast Cancer Recurrence. Clin. Biochem. 2012, 45, 1503–1505. [CrossRef]
50. Balci, H.; Genc, H.; Papila, C.; Can, G.; Papila, B.; Yanardag, H.; Uzun, H. Serum Lipid Hydroperoxide Levels and Paraoxonase
Activity in Patients With Lung, Breast, and Colorectal Cancer. J. Clin. Lab. Anal. 2012, 26, 155–160. [CrossRef]
51. Camps, J.; Marsillach, J.; Joven, J. Measurement of Serum Paraoxonase-1 Activity in the Evaluation of Liver Function. World J.
Gastroenterol. 2009, 15, 1929–1933. [CrossRef] [PubMed]
52. Mazzuferi, G.; Bacchetti, T.; Islam, M.O.; Ferretti, G. High Density Lipoproteins and Oxidative Stress in Breast Cancer. Lipids
Health Dis. 2021, 20, 143. [CrossRef]
Nutrients 2024, 16, 3579 13 of 13

53. Pan, X.; Huang, L.; Li, M.; Mo, D.; Liang, Y.; Liu, Z.; Huang, Z.; Huang, L.; Liu, J.; Zhu, B. The Association between PON1 (Q192R
and L55M) Gene Polymorphisms and Risk of Cancer: A Meta-Analysis Based on 43 Studies. BioMed Res. Int. 2019, 2019, 5897505.
[CrossRef]
54. Lou-Bonafonte, J.M.; Gabás-Rivera, C.; Navarro, M.A.; Osada, J. PON1 and Mediterranean Diet. Nutrients 2015, 7, 4068–4092.
[CrossRef] [PubMed]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.