Breast Cancer: Mechanisms, Pathways, Targets, and Evidence-Based Therapeutic Approaches

Breast cancer represents one of the most prevalent malignancies worldwide and stands as the second leading cause of cancer-associated mortality in women. The complexity of breast cancer extends beyond a single condition to encompass diverse molecular subtypes with distinct biological behaviors, treatment responses, and clinical outcomes. This comprehensive report examines the fundamental mechanisms driving breast cancer pathogenesis, key signaling pathways involved, molecular targets for therapeutic intervention, and the spectrum of treatment approaches with varying levels of evidence supporting their efficacy. Through understanding these aspects, we can better appreciate both established therapies with strong clinical evidence and emerging approaches that show promise but require further validation.

Understanding Breast Cancer Fundamentals

Breast cancer is characterized by the uncontrolled growth of abnormal cells in breast tissue, originating primarily in the milk-producing ducts or glandular tissues. The disease encompasses several distinct molecular subtypes defined primarily by the expression of specific receptors. Traditional classification divides breast cancers based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression into hormone receptor-positive (ER+ and/or PR+), HER2-positive, and triple-negative breast cancer (TNBC) which lacks expression of all three receptors91518.

Recent refinements to breast cancer classification have introduced additional categories, including "HER2-low" breast cancer, characterized by low HER2 protein expression without gene amplification. This category has gained clinical relevance with the development of antibody-drug conjugates that show efficacy in this patient population113. The accurate definition of this subtype remains challenging, with efforts underway to refine classification criteria to identify patients eligible for these targeted therapies.

Triple-negative breast cancer has been further classified into six distinct subtypes based on gene expression profiling: two basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype15. Each subtype displays unique gene expression patterns and biological behaviors, which translate to different therapeutic vulnerabilities and clinical outcomes.

The molecular complexity of breast cancer extends beyond receptor status to encompass alterations in numerous cellular pathways, genetic mutations, and epigenetic modifications. This complexity necessitates a multifaceted approach to both understanding breast cancer biology and developing effective therapeutic strategies.

Molecular Pathogenesis Mechanisms

The development and progression of breast cancer involve multifaceted molecular mechanisms that disrupt normal cellular processes and drive malignant transformation. These mechanisms encompass genetic alterations, epigenetic modifications, hormonal influences, and metabolic reprogramming.

Genetic factors play a fundamental role in breast cancer pathogenesis. Mutations in specific genes such as BRCA1 and BRCA2 significantly increase susceptibility to breast cancer by disrupting DNA repair mechanisms. BRCA1 is involved in homologous recombination, a critical pathway for repairing double-strand DNA breaks, but also stimulates nucleotide excision repair (NER), which processes a broad spectrum of DNA damage and maintains genomic stability10. Deficiencies in these repair mechanisms lead to genomic instability, facilitating the accumulation of additional genetic alterations that drive tumorigenesis.

Epigenetic modifications represent another crucial dimension in breast cancer pathogenesis. These reversible changes to chromatin structure alter gene expression without changing the underlying DNA sequence. The emerging role of epigenetic modifiers in breast cancer development and therapeutic response has gained significant attention2. The interaction between BRCA1 and GADD45A (growth arrest and DNA damage-inducible protein GADD45 alpha) exemplifies this mechanism, potentially influencing breast cancer development through nucleotide excision repair stimulation and local active demethylation of genes important for malignant transformation10.

Recent research has revealed the importance of RNA modifications in breast cancer progression. The N6-methyladenosine (m6A) demethylase ALKBH5 promotes resistance to HER2-targeted therapy by enhancing m6A demethylation of GLUT4 mRNA, increasing its stability and resulting in enhanced glycolysis in resistant breast cancer cells11. This mechanism illustrates how epigenetic regulation at the RNA level can influence metabolic reprogramming, a hallmark of cancer that supports rapid proliferation and survival under stress conditions.

Hormonal influences constitute a fundamental aspect of breast cancer biology, particularly in hormone receptor-positive disease. The interplay between estrogen and progesterone signaling pathways regulates cellular proliferation, differentiation, and survival in breast tissue, with dysregulation contributing to carcinogenesis20. In the normal breast, progesterone promotes differentiation rather than growth, suggesting a complex role in breast cancer development that challenges simplified views of its function.

Obesity has emerged as a significant factor in breast cancer pathogenesis through multiple mechanisms: promoting insulin resistance leading to type 2 diabetes, upregulating aromatase resulting in elevated serum estrogen levels, and stimulating the release of reactive oxygen species (ROS) by macrophages6. Increased circulating glucose activates the mammalian target of rapamycin (mTOR) signaling pathway, which plays a crucial role in breast cancer development. The association between body mass index and breast cancer incidence highlights the importance of metabolic factors in breast cancer risk.

Key Signaling Pathways in Breast Cancer

The dysregulation of cellular signaling pathways represents a fundamental aspect of breast cancer pathogenesis, driving uncontrolled proliferation, survival, and metastasis. Several key pathways have been implicated in breast cancer development and progression, offering potential targets for therapeutic intervention.

The PI3K/AKT/mTOR (PAM) signaling pathway has emerged as a central player in breast tumorigenesis, conferring worse prognosis when aberrantly activated7. This pathway begins with phosphatidylinositol 3-kinase (PI3K) activation, leading to downstream signaling through protein kinase B (PKB/AKT) and ultimately to the mechanistic target of rapamycin (mTOR). The PAM pathway regulates numerous cellular processes including cell growth, proliferation, survival, and metabolism. Different breast cancer subtypes exhibit varying frequencies and mechanisms of PAM pathway alterations, necessitating subtype-specific approaches to targeting this pathway7.

Hedgehog (Hh) signaling represents another critical pathway in breast cancer. Essential for embryonic development, tissue regeneration, and stem cell renewal, Hedgehog signaling plays important roles in breast cancer through both canonical and non-canonical mechanisms14. The contribution of Hedgehog signaling varies according to the molecular, clinical, and histopathological characteristics of breast cancer, with particular relevance for disease progression and metastasis. This pathway has been explored as a potential therapeutic target, with several agents showing efficacy in preclinical models and undergoing evaluation in clinical trials.

The epidermal growth factor receptor (EGFR) axis constitutes a significant signaling pathway, particularly in triple-negative breast cancer (TNBC). While targeted therapies have transformed outcomes for hormone-positive and HER2-positive breast cancers, TNBC lacks clinically approved targeted therapies, creating an urgent need to identify effective therapeutic targets18. EGFR emerges as a promising target for TNBC, though resistance mechanisms present challenges that necessitate combination therapeutic approaches.

Hormone receptor signaling pathways, including estrogen and progesterone receptor signaling, dominate the landscape of hormone receptor-positive breast cancers. The complex interactions between these pathways influence cellular behavior and therapeutic responses. Multiple clinical studies have found that progestins were as effective as tamoxifen at improving progression-free survival in ER-positive breast cancer, challenging simplified views of progesterone's role in breast cancer progression20.

Enhancer transcription represents an emerging mechanism linking transcription factor binding to gene expression control in breast cancer. Subtype-specific transcription factors act at transcribed enhancers to dictate gene expression patterns determining growth outcomes17. Key factors identified include Forkhead transcription factors, FOSL1, and PLAG1. FOSL1, a Fos family transcription factor, is highly enriched at enhancers in TNBC cells and acts as a key regulator of proliferation and viability specifically in TNBC cells but not Luminal A cells, associated with poor prognosis in TNBC patients17.

Molecular Targets and Therapeutic Strategies

The diversity of breast cancer subtypes necessitates tailored therapeutic approaches that target specific molecular vulnerabilities. The evolution of targeted therapies has transformed the treatment landscape, with varying levels of evidence supporting different approaches.

Established Therapeutic Targets

Estrogen receptor targeting represents the cornerstone of treatment for hormone receptor-positive breast cancer. Endocrine therapies such as selective estrogen receptor modulators (e.g., tamoxifen), aromatase inhibitors, and selective estrogen receptor degraders have demonstrated substantial efficacy in reducing recurrence and improving survival18. These approaches have robust clinical evidence supporting their use as both adjuvant and metastatic therapies.

HER2-directed therapies have revolutionized outcomes for patients with HER2-positive breast cancer. Monoclonal antibodies (e.g., trastuzumab, pertuzumab), antibody-drug conjugates (e.g., T-DM1), and tyrosine kinase inhibitors (e.g., lapatinib) targeting HER2 have demonstrated significant clinical benefit1118. Recent developments have expanded the potential of HER2-directed therapies beyond classical HER2-positive disease to include "HER2-low" breast cancers, with antibody-drug conjugates showing efficacy in this patient population113.

For triple-negative breast cancer, molecular subtyping based on gene expression profiles has emerged as an approach to guide therapy selection. The six distinct TNBC subtypes display unique therapeutic vulnerabilities: basal-like subtypes preferentially respond to cisplatin, mesenchymal subtypes to PI3K/mTOR inhibitors and abl/src inhibitors, and luminal androgen receptor subtypes to androgen receptor antagonists15. This personalized approach represents an evidence-based strategy to address the heterogeneity of TNBC.

Neoadjuvant therapy—treatment administered before primary surgery—has substantial evidence supporting its use in specific breast cancer contexts. Appropriate candidates include patients with inflammatory breast cancer and those in whom residual disease may prompt a change in therapy3. For triple-negative breast cancer, anthracycline- and taxane-containing regimens are recommended, with the option of adding carboplatin to increase pathologic complete response rates3.

Emerging Therapeutic Targets

The PAM pathway (PI3K/AKT/mTOR) represents a promising target for breast cancer therapy. Several inhibitors targeting key nodes in this pathway—PI3K, AKT, and mTOR—have been developed, with some already approved for specific breast cancer populations7. These agents have shown particular promise in hormone receptor-positive breast cancer, often in combination with endocrine therapy to overcome or delay resistance.

Epigenetic modifiers present emerging therapeutic targets in breast cancer. The role of histone-modifying enzymes in perturbing the tumor environment provides a rationale for targeting chromatin-modifying enzymes2. Preclinical studies have connected epigenetic activity with changes in cells that support oncogenic growth, though translation to clinical applications remains an active area of investigation.

The N6-methyladenosine (m6A) demethylase ALKBH5 has emerged as a potential target in HER2-positive breast cancer resistant to standard therapies. Elevated expression of ALKBH5 confers resistance to HER2-targeted therapy through m6A demethylation of GLUT4 mRNA, enhancing glycolysis11. Targeting the ALKBH5/GLUT4 axis shows therapeutic potential for breast cancer patients refractory to HER2-targeted therapies, with suppression of GLUT4 via genetic knockdown or pharmacological targeting restoring sensitivity to trastuzumab and lapatinib both in vitro and in vivo11.

The Hedgehog signaling pathway represents another emerging target, particularly relevant for breast cancer progression and metastasis14. Several agents targeting different components of the Hedgehog pathway have shown efficacy in preclinical models and are being evaluated in clinical trials, though their specific role in breast cancer therapy continues to be defined.

Alternative and Complementary Approaches

Botanical remedies for breast cancer management show varying levels of evidence. Approximately 80% of women diagnosed with breast cancer have turned to alternative or supplementary therapies8. Botanical extracts have demonstrated potential as anticancer agents with reduced toxicity and excellent safety profiles. Clinical investigations have examined ten herbs in breast cancer management, including black cohosh, ginseng, ashwagandha, garlic, turmeric, green tea, black seed, flaxseed, guarana, and peppermint8. The most established applications involve symptom management rather than direct anticancer effects: easing chemotherapy-induced nausea and vomiting, mitigating hot flashes caused by hormonal therapy, reducing skin inflammation from radiotherapy, and alleviating gastrointestinal symptoms.

Conservative non-pharmacological treatments for chemotherapy-induced peripheral neuropathy (CIPN) represent another area with emerging evidence. Various interventions including acupuncture, physiotherapy, cryotherapy, and yoga have been examined, with evidence remaining controversial12. Moderate exercise and stress-reducing activities show potential benefit for managing CIPN symptoms, though further research is needed to establish optimal approaches.

Alternative mental health interventions for breast cancer patients address the psychological impact of diagnosis and treatment. For Hispanic women with breast cancer, four alternative interventions have significantly addressed cultural mental health needs, with mindfulness and technology use being the most studied approaches4. These interventions improved overall quality of life, though further research is needed to address psychological distress in culturally appropriate ways.

Mechanisms of Resistance and Therapeutic Challenges

Treatment resistance remains a significant challenge across breast cancer subtypes, driven by diverse molecular mechanisms that limit therapeutic efficacy. Understanding these resistance mechanisms is crucial for developing strategies to overcome them and improve patient outcomes.

Resistance to HER2-targeted therapy represents a significant challenge for patients with HER2-positive breast cancer. The upregulation of the N6-methyladenosine (m6A) demethylase ALKBH5 has been identified as a mechanism of resistance to trastuzumab and lapatinib11. ALKBH5 promotes m6A demethylation of GLUT4 mRNA, increasing GLUT4 mRNA stability and enhancing glycolysis in resistant breast cancer cells. Targeting this pathway through GLUT4 suppression restores sensitivity to HER2-targeted therapies, highlighting the potential of combination approaches to overcome resistance.

For hormone receptor-positive breast cancer, endocrine therapy resistance often develops through multiple mechanisms including estrogen receptor mutations, altered expression of coregulators, activation of growth factor signaling pathways (particularly PI3K/AKT/mTOR), and phenotypic changes such as epithelial-mesenchymal transition7. Combination approaches targeting both estrogen receptor signaling and alternative pathways show promise for overcoming or delaying resistance.

Triple-negative breast cancer presents unique challenges due to its heterogeneity and lack of well-defined therapeutic targets. The identification of six distinct molecular subtypes with different therapeutic vulnerabilities represents a step toward more effective targeting15. However, intratumoral heterogeneity and adaptive resistance mechanisms continue to limit therapeutic efficacy, necessitating combination approaches and sequential treatment strategies.

The tumor microenvironment plays a crucial role in therapeutic resistance across breast cancer subtypes. Interactions between cancer cells and stromal components, including immune cells, fibroblasts, and extracellular matrix, influence drug penetration, cellular signaling, and phenotypic plasticity. Strategies targeting both cancer cells and their microenvironment show promise for overcoming resistance mechanisms.

Epigenetic alterations contribute to therapeutic resistance through dynamic regulation of gene expression and cellular phenotype. Reversible modifications to histones and DNA influence transcriptional programs and cellular plasticity, enabling adaptation to therapeutic pressures2. Targeting epigenetic modifiers in combination with conventional therapies represents a potential strategy to overcome resistance and enhance therapeutic efficacy.

Conclusion

Breast cancer represents a complex and heterogeneous disease with diverse molecular subtypes, each characterized by distinct pathogenesis mechanisms, signaling pathway alterations, and therapeutic vulnerabilities. The comprehensive understanding of these underlying biological processes has revolutionized treatment approaches, moving from generalized cytotoxic therapies toward precision medicine strategies tailored to specific molecular targets.

The evolving landscape of breast cancer classification continues to refine our understanding of disease subtypes, with recent developments such as the identification of HER2-low breast cancer and the subclassification of triple-negative breast cancer into six distinct molecular subtypes. These refinements enable more precise therapeutic targeting and improve patient outcomes through personalized treatment approaches.

Evidence-based therapeutic strategies vary considerably across breast cancer subtypes. For hormone receptor-positive disease, endocrine therapy remains the cornerstone of treatment, while HER2-targeted approaches have transformed outcomes for HER2-positive breast cancer. The challenging landscape of triple-negative breast cancer is gradually yielding to molecular subtyping approaches that match specific vulnerabilities with appropriate targeted agents.

Alternative and complementary approaches demonstrate varying levels of evidence, with most showing potential benefit for symptom management rather than direct anticancer effects. As research continues to unravel the complex biology of breast cancer, novel therapeutic targets and approaches will likely emerge, further enhancing our ability to effectively manage this prevalent malignancy.

The future of breast cancer management lies in increasingly personalized approaches that integrate molecular profiling, genetic testing, and targeted therapies to optimize outcomes while minimizing adverse effects. Continued research into resistance mechanisms and combination strategies will be essential to address the persistent challenges of treatment resistance and disease recurrence. By building on our current understanding of breast cancer biology and leveraging emerging technologies and therapeutic modalities, we can continue to improve outcomes for patients across the spectrum of breast cancer subtypes.