Angiogenesis of Breast Cancer

Angiogenesis, the process of new blood vessel formation, plays a central role in both local tumor growth and distant metastasis in breast cancer. Extensive laboratory data suggest that angiogenesis plays an essential role in breast cancer development, invasion, and metastasis. Hyperplastic murine breast papillomas and histologically normal lobules adjacent to cancerous breast tissue support angiogenesis in preclinical models, suggesting that angiogenesis precedes transformation of mammary hyperplasia to malignancy. Transfection of tumor cells with angiogenic stimulatory peptides has been shown to increase tumor growth, invasiveness, and metastasis. Conversely, transfection of tumor cells with inhibitors of angiogenesis decreases growth and metastasis. The matrix metalloproteinase (MMP) family of enzymes degrades the basement membrane and extracellular matrix and is associated with a family of endogenous inhibitors, tissue inhibitors ofmetalloproteinases (TIMPs). Under normal physiologic conditions, the MMPs and TIMPs exist in anexquisitebalance.Thisbalance isdisrupted during active angiogenesis. Expression of MMPs increases with the progression from benign to preinvasive, invasive, and metastatic breast cancer and is associated with increasing histologic tumor grade. Microscopic metastases are growth restricted and remain dormant until they undergo an angiogenic switch, presumably a result of further mutation. This angiogenic switch often results in increased expression of MMPs. Hypoxia is a key signal for the induction of angiogenesis. Hypoxia-inducible factors (HIF-1 and HIF-2) are heterodimeric transcription factors consisting of and subunits. The subunit is constitutively expressed while the subunit is protected from degradation only under hypoxic condition. HIF-1 expression progressively increases from normal breast tissue to usual ductal hyperplasia to ductal carcinoma-insitu to invasive ductal carcinoma. HIF-1 expression is higher in poorly differentiated than in well-differentiated lesions and is associated with increased proliferation and expression of the estrogen receptor and vascular endothelial growth factor (VEGF). Similarly, expression of carbonic anhydrase IX, an HIF-1 -dependant enzyme important in pH regulation, is associated with worse relapse-free and overall survival in patients with invasive breast cancer.