Pathophysiology describes the biological mechanisms that generate and advance a disease, explaining how normal processes become dysfunctional. Breast cancer begins when epithelial cells lining the milk ducts or lobules lose their normal growth control. This leads to the uncontrolled proliferation of transformed cells, forming a localized tumor that can eventually spread to distant sites. Understanding this progression is necessary for developing effective prevention and treatment strategies.
Cellular Transformation and Genetic Instability
Breast cancer originates from a breakdown in the cell’s internal machinery, driven by accumulating genetic defects. This shift is characterized by genomic instability, an increased tendency for the cell’s DNA to sustain and retain alterations during division. This instability allows a normal cell to acquire the multiple mutations necessary for malignant transformation.
Genome integrity is maintained by caretaker genes, such as the tumor suppressors BRCA1 and BRCA2, which are responsible for DNA repair. When these genes are mutated or damaged, their repair function is impaired, leading to chromosomal instability (CIN). This results in numerical and structural abnormalities, causing gene losses or gains that dramatically alter cell function.
Genetic errors also affect cell division and survival regulation. Proto-oncogenes, which normally promote growth, can become hyperactive oncogenes (e.g., MYC), leading to sustained proliferative signaling. Simultaneously, tumor suppressor genes like TP53, which triggers cell death when damage is irreparable, can be inactivated. The dual effect of unchecked growth promotion and the failure of apoptosis allows damaged cells to survive and proliferate indefinitely, forming the primary tumor.
The failure of apoptosis (programmed cell death) is a defining feature, ensuring that cells with unstable genomes are not eliminated. This resistance to cell death, combined with the loss of cell cycle checkpoints, provides a significant survival advantage. This ensures the rapid evolution of the cancer cell population, allowing it to adapt to microenvironmental pressures and progress toward a more aggressive phenotype.
Molecular Subtypes and Signaling Pathways
Modern classification relies on identifying specific molecular markers that dictate tumor behavior and treatment response. This classification is based on the presence or absence of three key receptors: the Estrogen Receptor (ER), the Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2). These receptors act as signaling pathways, responding to external stimuli that “feed” the tumor’s growth.
The Luminal A subtype, the most common, is ER-positive and/or PR-positive, but HER2-negative, and generally features a slower growth rate. When bound by hormones, these receptors activate signaling cascades that drive cell division and survival. Luminal B tumors are also hormone receptor-positive but have a higher proliferative rate, often due to being HER2-positive or having high expression of the proliferation marker Ki-67.
Cancers classified as HER2-enriched are negative for both ER and PR but overexpress the HER2 protein, often through gene amplification. HER2 overexpression leads to the overactivation of proto-oncogenic signaling pathways, resulting in aggressive, uncontrolled cell growth. Targeted therapies have been developed to block this specific pathway, significantly improving outcomes for this subtype.
The third major category is Triple Negative Breast Cancer (TNBC), defined by the absence of all three receptors: ER, PR, and HER2. Lacking these common targets, TNBC is typically treated with traditional chemotherapy and is associated with a more aggressive clinical course and higher recurrence rates. TNBC is not a single disease entity and can be further subdivided based on other genetic features, such as those that express the Androgen Receptor (AR).
Tumor Microenvironment and Angiogenesis
A breast tumor is a complex, self-sustaining ecosystem known as the tumor microenvironment (TME). The TME consists of non-cancerous cells, including fibroblasts, immune cells, and blood vessels, which are manipulated by cancer cells to support growth and progression. For example, cancer cells recruit immune cells, such as Tumor-Associated Macrophages (TAMs), which can switch from an anti-tumor to a pro-tumor state.
These recruited cells and the surrounding matrix secrete factors that promote tumor growth and suppress the immune response. A primary process orchestrated by the TME is angiogenesis, the formation of new blood vessels from existing vasculature. To grow beyond a few millimeters, the tumor must secure a reliable supply of oxygen and nutrients.
Cancer cells induce an “angiogenic switch” by releasing pro-angiogenic factors, notably Vascular Endothelial Growth Factor (VEGF). VEGF stimulates endothelial cells lining nearby blood vessels to proliferate and sprout new capillaries toward the tumor. This new vessel network supports the tumor’s metabolic demands and provides routes for cancer cells to disseminate and metastasize.
Mechanisms of Metastasis
Metastasis, the spread of cancer cells from the primary tumor to distant organs, is the most life-threatening aspect of breast cancer. This progression involves a multi-step cascade that cancer cells must successfully navigate. The first step is local invasion, where cancer cells break through the basement membrane and infiltrate the surrounding stromal tissue.
To facilitate invasion, cancer cells often undergo Epithelial-Mesenchymal Transition (EMT), transforming stationary epithelial cells into mobile, invasive cells. The cells then enter the bloodstream or lymphatic system through intravasation, often exploiting leaky tumor blood vessels. Once in circulation, they must survive stressors like immune surveillance and fluid shear stress, frequently traveling in protective clusters.
The circulating tumor cells eventually adhere to the endothelial lining of a distant capillary bed and exit the circulation through extravasation. This exit requires the cells to breach the vessel wall, sometimes by releasing enzymes like matrix metalloproteinases (MMPs) to break down the barrier. The final stage is colonization, where the cancer cells must adapt to the new organ microenvironment and begin to proliferate, forming a detectable secondary tumor.
The choice of colonization site is not random, often following the “seed and soil” theory. Here, cancer cells (“seed”) preferentially establish themselves in favorable distant organs (“soil”). For breast cancer, common sites include the bones, lungs, liver, and brain, which provide the specific growth factors and stromal support necessary for the cancer cells to thrive.