Emerging Role and Mechanism of Markers in Breast Cancer
Tooba Kashaf 1, Risha Raman 2, Zubair Sharif 3
1Department of Medical Laboratory, Technology, Superior University Lahore, Pakistan,
Email
[email protected]2Department of Medical Laboratory, Technology, Superior University Lahore, Pakistan,
Email
[email protected]3Department of Medical Laboratory, Technology, Superior University Lahore, Pakistan,
Email
[email protected] Abstract: Breast cancer is among the most common cancers worldwide, primarily affecting
women but also occurring in men. While its exact cause remains unknown, several risk factors
have been identified, including age, family history, genetic mutations (BRCA1, BRCA2),
hormonal influences, lifestyle, and environmental exposures. Recent research has highlighted
various genetic, epigenetic, and proteasomal markers that improve diagnosis and treatment.
Key biomarkers include BRCA1/BRCA2, Ki67, p53, Cyclin D1 mutation, TP53 mutation,
HER2 amplification, DNA methylation patterns, microRNAs (miRNAs), and androgen
receptors (ARs). These markers play a crucial role in personalized medicine, enabling precise
diagnosis and tailored therapies. For instance, HER2 amplification helps determine suitability
for targeted treatments like trastuzumab. Similarly, miRNAs regulate gene expression, offering
insights into tumor behavior and therapeutic response.
Despite advancements, identifying the most effective biomarkers remains a challenge for
researchers and clinicians. Optimizing these markers could enhance treatment strategies,
reduce costs, and improve patient outcomes. Ongoing investigations into emerging biomarkers
may lead to better interventions, ultimately supporting breast cancer management and care.
Keywords: Breast Cancer, BRCA1/BRCA2, Triple-Negative Breast Cancer (TNBC),
miRNAs, Precision Medicine, Liquid Biopsies
Introduction: Breast cancer is a global health problem and a leading cause of cancer-related
death in women. Breast cancer, including its various subtypes, is characterized by its
association with biological and medical conditions. Early detection and treatment are important
to reduce mortality. Global Searching; The global spread of breast cancer requires extensive
research into its causes, diagnosis, and treatment. According to the World Health Organization,
there are approximately 2.3 million new cancer cases each year, accounting for 11.7% of all
cancer cases worldwide. International collaborations and clinical trials have improved our
understanding and led to the identification of important biomarkers and treatment strategies
[1].Awareness; Raising awareness about breast cancer through awareness campaigns and
education has increased the rate of early detection. Services including self-examination,
mammograms and regular check-ups encourage people to seek timely treatment. Importance;
The importance of understanding breast cancer lies in its impact on public health.
Comprehensive research into its molecular underpinnings can guide the development of
personalized treatment approaches, improving patient outcomes and quality of life.
Pathogenesis; Breast cancer is caused by genetic and epigenetic changes that affect cellular
processes. Mutations in tumor suppressor genes such as BRCA1 and TP53 and changes in
genes such as DNA methylation play an important role in cancer. These changes lead to
uncontrolled cell proliferation, invasion, and metastasis. Cyclin D1 is a cell cycle regulator that
is frequently overexpressed in breast cancer, causing cell cycle disruption and tumor growth
[2,3]. Biomarkers; Biomarkers are measurable indicators of biological processes, pathogenic
organisms, or pharmacological responses. In breast cancer, biomarkers aid in diagnosis,
prognosis, and treatment decisions. They include genetic markers such as BRCA mutations,
epigenetic markers such as DNA methylation, proteasome markers such as HER2
overexpression, and proteins such as p53 and cyclin D1. These biomarkers help stratify patients
and guide treatment strategies. The Relationship Between Cancer and Biomarkers; The
interaction between cancer and biomarkers is important for understanding the disease.
Biomarkers provide information about cancer biology and allow patients to be stratified for
treatment. For example, HER2-positive tumors respond well to trastuzumab, demonstrating the
clinical utility of a biomarker-driven approach. In addition, p53 mutations are common in many
breast cancers, especially in stage III tumors, and are associated with poor prognosis [4].
Overexpression of cyclin D1 is associated with hormone receptor-positive isoforms and may
serve as a target for endocrine therapy[5]. Sign Symptoms; Common signs and symptoms of
breast cancer include palpable lumps, changes in breast shape or size, skin dimpling, nipple
discharge, and localized pain. Advanced cases may present with systemic symptoms like
weight loss and fatigue. Early recognition of these signs is crucial for prompt intervention.
Treatment; Treatment modalities for breast cancer include surgery, radiation therapy,
chemotherapy, targeted therapy, and immunotherapy. The choice of treatment depends on the
tumor subtype, stage, and patient characteristics. Multidisciplinary approaches have shown
improved efficacy in managing the disease. Drugs; Drugs used to treat cancer range from
chemotherapy drugs such as doxorubicin and paclitaxel to treatments such as trastuzumab and
PARP inhibitors. Hormone therapy, such as tamoxifen and aromatase inhibitors, are effective
in the hormone receptor-positive subtype. Emerging drugs, including cyclin-dependent kinase
(CDK) inhibitors that target the cyclin D1 pathway, have been investigated in clinical trials and
hold promise for providing new treatments [6].
Prevalence Rate of Breast Cancer. Breast cancer is one of the most common cancers
worldwide, significantly contributing to cancer-related morbidity and mortality: Global
Prevalence As of 2020, breast cancer was the most diagnosed cancer globally, with 2.3 million
new cases, accounting for 11.7% of all cancer cases [7]. Developed Countries; Higher
Figure 1: Prevalence Rate of Breast Cancer
prevalence due to longer life expectancy, increased screening, and lifestyle changes. For
example, in the United States, approximately 264,000 cases are diagnosed annually, with
42,000 deaths [8]. Developing Countries; Rapidly increasing prevalence due to urbanization,
changing reproductive patterns, and limited access to healthcare. In India, the age-standardized
incidence rate is 25.8 per 100,000 women [9]. Gender-Specific Prevalence; While
predominantly affecting women, breast cancer also occurs in men, constituting about 1% of all
breast cancer diagnoses [10]. Age-Specific Prevalence; The risk of breast cancer increases
with age, with the highest incidence in women aged 50 and older. Younger women (below 40)
represent 5–7% of cases but often present more aggressive forms [11].
1. Emerging Biomarkers in Breast Cancer:Biomarkers play a crucial role in diagnosing,
predicting prognosis, and guiding treatment strategies for breast cancer. They can be broadly
categorized into genetic, epigenetic, and proteomic markers. BRCA1/BRCA2; Mutations in
BRCA1/BRCA2 increase breast cancer risk by impairing DNA repair mechanisms through
homologous recombination. Individuals with these mutations face a lifetime breast cancer risk
of up to 72% [12,13].TP53 Mutations; Found in approximately 20% of breast cancer cases,
TP53 mutations are associated with aggressive tumor phenotypes and poor prognosis [13].
HER2 Amplification; HER2-positive breast cancer accounts for 15–20% of all cases and is
linked to increased tumor growth and metastasis [14]. DNA Methylation; Aberrant
methylation of tumor suppressor genes, such as RASSF1A, is frequently observed in breast
cancer. Methylation analysis is emerging as a non-invasive diagnostic tool [15]. MicroRNAs
(miRNAs): MiRNAs like miR-21 and miR-155 act as oncogenes by modulating pathways
related to apoptosis and immune evasion [11,12].Proteomic Markers: Ki67: A marker of cell
proliferation, Ki67 is widely used to assess tumor aggressiveness and guide treatment decisions
[16]. p53 and CyclinD1: These markers regulate cell cycle progression and apoptosis. Altered
expression is indicative of poor treatment outcomes [17]. Androgen Receptor (AR): While
traditionally studied in prostate cancer, AR expression in breast cancer has gained attention for
its potential as a therapeutic target, particularly in triple-negative breast cancer (TNBC) [18].
Significance: By categorizing breast cancer subtypes, these biomarkers enable tailored
therapeutic approaches, improving outcomes for patients with aggressive or recurrent disease
[16].
2. Role and Mechanisms of Key Biomarkers: Biomarkers do not merely serve as diagnostic
tools but also provide insights into the molecular mechanisms driving breast cancer:
BRCA1/BRCA2: These genes encode proteins essential for homologous recombination repair.
Loss-of-function mutations lead to genomic instability, increasing susceptibility to DNA-
damaging agents like PARP inhibitors [6,7]. HER2: Amplification of HER2 drives oncogenic
signaling through pathways like PI3K-AKT and MAPK, leading to increased tumor
proliferation and survival. HER2-targeted therapies like trastuzumab inhibit these pathways,
reducing tumor growth [9,17]. miRNAs: MiR-155 downregulates tumor suppressor genes,
while let-7 family miRNAs suppress oncogenic pathways. These regulatory RNAs are crucial
in maintaining tumor plasticity and promoting metastasis [11,18]. Ki67: Elevated Ki67
expression reflects high cellular proliferation and is associated with poor prognosis. However,
its prognostic utility varies between molecular subtypes of breast cancer [13]. p53: Loss of p53
function impairs apoptosis, allowing cancer cells to evade programmed cell death, a hallmark
of tumorigenesis [14]. Clinical Insights: Understanding these mechanisms facilitates the
development of biomarkers not only for early detection but also for predicting response to
therapies like immunotherapy and targeted treatments [19].
3. Diagnostic and Therapeutic Applications: Biomarkers have revolutionized the clinical
management of breast cancer through their application in diagnostics, treatment, and
prognostication. Diagnostics: HER2 Testing: HER2 testing using immunohistochemistry
(IHC) and fluorescence in situ hybridization (FISH) is standard for identifying candidates for
trastuzumab therapy [9,17]. Liquid Biopsies: Non-invasive methods like liquid biopsies
analyze circulating tumor DNA (ctDNA), enabling early detection and monitoring of minimal
residual disease [20]. Therapeutics: HER2-Targeted Therapies; Drugs like trastuzumab and
pertuzumab specifically inhibit HER2 signaling, significantly improving survival in HER2-
positive patients [17,21]. PARP Inhibitors: Olaparib and talazoparib target BRCA-mutant
cancers by exploiting defects in DNA repair mechanisms [6,22]. miRNA-Based Therapies:
Therapeutic approaches aim to restore normal miRNA function by either inhibiting oncogenic
miRNAs or mimicking tumor-suppressive miRNAs [11,23]. Prognostics: Markers like Ki67
and p53 are used to stratify patients into low-risk and high-risk groups, guiding the need for
adjuvant therapies [13,14]. Advances: Integrating biomarkers into clinical workflows has
significantly improved the precision of breast cancer treatment, offering new hope for patients
with advanced or resistant disease [19,24].
4. Challenges and Future Directions: Despite significant progress, several challenges impede
the full realization of biomarker potential. Challenges: Tumor Heterogeneity: Genetic and
molecular differences within tumors complicate the identification of universal biomarkers [25].
Validation Standards: The lack of standardized protocols for biomarker validation limits their
clinical utility [26]. Triple-Negative Breast Cancer (TNBC): This subtype lacks established
therapeutic targets, necessitating novel biomarkers to guide treatment [15,27]. Future
Directions: Multi-Omics Integration: Combining genomics, proteomics, and metabolomics
offers a holistic view of tumor biology, paving the way for novel biomarker discovery [28].
Artificial Intelligence (AI): AI-driven platforms analyze complex datasets to uncover
biomarker patterns and predict therapeutic responses [29]. Liquid Biopsies: Advances in
detecting ctDNA and exosomal RNA are enabling real-time tumor monitoring, particularly in
metastatic settings [20,30]. Immunotherapy Markers: Identifying biomarkers like PD-L1 and
tumor mutation burden could enhance patient selection for immune checkpoint inhibitors [31].
Figure 2: challenges and Future Directions in Biomarker Research
Conclusion: Breast cancer remains a major problem worldwide, with 2.3 million new cases
each year, making it the most common cancer and leading cause of cancer worldwide [37]. Its
prevalence varies by region; developing countries face higher costs due to increasing life
expectancy and living conditions, while developing countries are exacerbated by rapid
urbanization and limited access to healthcare [38,39]. Although breast cancer primarily affects
women, it also affects men, albeit at a lower rate, accounting for approximately 1% of all
diagnoses [40]. The discovery of cancer biomarkers is important for diagnosis, prognosis, and
treatment. Genetic markers such as BRCA1/BRCA2, TP53, and HER2 amplification play an
important role in determining risk and tailoring treatment. For example, HER2-targeting
therapies, such as trastuzumab, have improved the prognosis of HER2-positive patients
[41,42]. Similarly, epigenetic markers such as DNA methylation and miRNA provide
information about tumor behavior and have become important tools for noninvasive diagnosis
and targeted therapy [43,44]. Proteasome markers including Ki67, p53, and androgen receptor
(AR) further support patient outcomes and improve self-healing strategies [45]. Competition.
Tumor heterogeneity affects the universal use of biomarkers, and the lack of formal acceptance
criteria hinders their integration into routine therapy [46,47]. The lack of clear therapeutic
targets, especially in triple-negative breast cancer (TNBC), indicates an urgent need for novel
biomarker discovery [48]. Future directions in cancer research include the integration of multi-
omics technologies to provide comprehensive biomarker data and the use of artificial
intelligence to analyze difficult information to help make clear and immediate decisions
[49,50]. The increasing use of biopsy fluid and immunotherapies such as PD-L1 is expected to
change the breast cancer treatment landscape. These innovations, combined with continued
efforts in precision medicine, demonstrate the potential to reduce the global burden of cancer
and improve patient outcomes. An integrated approach that includes research, clinical practice,
and technology is essential to overcome current challenges and advance progress [51].
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