Interactions between estrogen and growth factor receptors in human breast cancers and the tumor-associated vasculature.

Estrogens and growth factors stimulate the proliferation of human breast cancer cells by primary binding and activation of specific receptors that regulate downstream signaling events. Receptors for estrogen are phosphoproteins, and the biologic function of these proteins can be modulated by changes in their phosphorylation state. Signal transduction by growth factor receptors, including HER-2/neu and epidermal growth factor (EGF) receptors, can alter the phosphorylation of estrogen receptor (ER) and the biologic activity of ER-dependent signaling networks both in the presence and in the absence of estrogenic ligands. In addition, both estrogen and growth factor signaling pathways regulate the secretion of vascular endothelial growth factors that stimulate tumor-associated angiogenesis. These molecular interactions significantly impact breast cancer cell growth and survival, and integration of selected signal transduction inhibitors with antiestrogen therapies show promise as a new antitumor treatment strategy that will soon be evaluated in the clinic. Sensitive and reliable assays of estrogen, HER-2/neu, and EGF receptors and tumor-associated angiogenesis will be important biologic factors to consider in the choice of optimal antitumor therapies for patients with breast cancer.