Pathophysiology of Breast Cancer
Breast cancer primarily originates from abnormal proliferation in the ductal and lobular epithelium, progressing through a spectrum of changes from hyperplasia to atypical hyperplasia, in situ carcinoma, and ultimately invasive carcinoma. 1
Cellular Origin and Progression
- Approximately 85-90% of invasive breast carcinomas are ductal in origin, while the remainder arise from lobular tissue 1
- The disease develops through a stepwise progression of proliferative abnormalities:
- Hyperplasia (excessive cell growth)
- Atypical hyperplasia (abnormal cell patterns)
- In situ carcinoma (cancer cells confined to ducts/lobules)
- Invasive carcinoma (cancer cells breaking through basement membrane) 1
- Certain variants of invasive ductal carcinoma have more favorable natural histories, including colloid/mucinous, adenoid cystic, and tubular carcinomas 1
Genetic Factors
- Hereditary mutations in BRCA1/BRCA2 genes account for 5-10% of breast cancer cases 2
- TP53 mutations are associated with Li-Fraumeni Syndrome, conferring up to 25% risk of breast cancer by age 74 3
- PTEN mutations (Cowden Syndrome) can confer up to 85% lifetime risk of breast cancer 3
- CDH1 mutations increase risk of lobular breast cancer by approximately 39% 3
- Moderate-penetrance genes include CHEK2, ATM, PALB2, and BRIP1, which contribute to breast cancer risk through DNA repair mechanism disruption 3
Molecular Subtypes and Biomarkers
- Breast cancer is classified based on molecular biomarkers that predict treatment response and prognosis 1:
- Hormone receptor status (estrogen receptor [ER], progesterone receptor [PR])
- Human epidermal growth factor receptor 2 (HER2) status
- Tumor grade and proliferation markers (e.g., Ki67) 1
- Triple-negative breast cancer (lacking ER, PR, and HER2) accounts for 15-20% of cases and presents significant therapeutic challenges due to its aggressive nature 4
Signaling Pathways
- Several key signaling pathways are deregulated in breast cancer development and progression:
- Estrogen receptor (ER) signaling pathway plays a crucial role in hormone-dependent breast cancers 5, 6
- HER2 pathway amplification leads to increased cell proliferation and survival in HER2-positive tumors 5
- Wnt/β-catenin pathway dysregulation affects stem cell proliferation, cell death, differentiation, and motility 5
- DNA repair pathways (including those involving BRCA1/2) when compromised lead to genomic instability 6, 7
Cancer Stem Cell Theory
- Emerging evidence suggests breast cancer may derive from mammary cancer stem cells 5
- These cells share characteristics with normal mammary stem cells but exhibit dysregulated self-renewal and differentiation 5
- Cancer stem cells may contribute to tumor heterogeneity, therapy resistance, and metastatic potential 5, 6
Hormonal Influences
- Endocrinologic and reproductive factors significantly impact breast cancer risk:
- Early menarche, late menopause, and nulliparity increase risk 7
- Estrogen exposure plays a complex role in breast carcinogenesis through:
- Receptor-mediated proliferative effects
- Potential DNA damage via metabolic activation
- Possible compromise of DNA repair systems 7
- Obesity may increase risk through increased leptin expression in adipose tissue 2
Epigenetic Regulation
- Epigenetic alterations contribute to breast cancer development through:
- DNA methylation changes affecting gene expression
- Histone modifications altering chromatin structure
- Non-coding RNAs regulating gene expression 5
- These mechanisms may contribute significantly to breast cancer heterogeneity and metastatic potential 5