Abstract
Despite the critical importance of ovarian steroids in the treatment of breast cancer, little is known about the acquisition or loss of estrogen and progesterone responsiveness in either the normal or neoplastic mammary gland. This review focuses on the interactions among mammary stroma-derived extracellular matrix (ECM) proteins, integrins and ovarian hormone-dependent proliferation in normal and neoplastic mammary cells both in vivo and in vitro. In vitro studies show that fibronectin is required for progesterone-induced proliferation of normal mammary epithelial cells and that specific ECM proteins also regulate interactions between growth factors and ovarian hormones. Studies with human breast cancer cell lines have shown that laminin inhibits estrogen-induced proliferation and estrogen-response-element-mediated transcription in vitro and also inhibits estrogen-induced proliferation in vivo. Reciprocally, ovarian steroids regulate the expression of ECM proteins and their cellular receptors, integrins, during mammary gland development in vivo. The fibronectin-specific integrin, alpha5beta1 is regulated by ovarian steroids and its expression is positively correlated with developmental stages of peak proliferation. These studies suggest that the coordinated regulation of ovarian hormone responsiveness and ECM/integrin expression may be critical to normal mammary gland development and breast cancer growth and progression.
Highlights
Postnatal mammary gland development and function are highly dependent upon the actions of the ovarian hormones, estrogen and progesterone [1]
To determine whether estrogen receptor (ER) is required in stromal tissue, epithelial tissue or both for normal mammary gland development, Cunha et al [3] have surgically transplanted wild-type (ER+/+) or ERKO (ER–/–) epithelial tissue with wild-type or ERKO stromal tissue under the kidney capsule of athymic nude mice. These authors reported that ER+/+ stroma was required for normal mammary ductal morphogenesis, but ER+/+ epithelium was not. These results corroborate in vitro studies that have demonstrated that estrogen-dependent mammary epithelial proliferation and/or ductal morphogenesis is mediated through the paracrine action of BM = basement membrane; ECM = extracellular matrix; EGF = epidermal growth factor; ER = estrogen receptor; ERE = estrogen response element; ERKO = estrogen receptor knockout; IGF-I = insulin-like growth factor-I; IGFBP = insulin-like growth factor binding protein; PR = progesterone receptor
Breast cancer is frequently classified by ER status, since absence of hormone responsiveness is associated with a poor prognosis and substantially limits therapy options
Summary
Postnatal mammary gland development and function are highly dependent upon the actions of the ovarian hormones, estrogen and progesterone [1]. Since specific ECM proteins influence mammary epithelial cell proliferative response to hormones and growth factors in vitro, it was of interest to investigate their roles in vivo Toward this end, we have analyzed the in vivo spatial and temporal concentrations of fibronectin, collagens I and IV and laminin during postnatal development, and the effects of ovariectomy and estrogen and progesterone treatment on ECM and integrin expression [17]. The tumors arising from laminin-treated MCF-7 cells continued to grow in the presence of the antiestrogen, with tumor size increasing more than 2-fold in 3 weeks These results indicate that the composition of ECM that surrounds tumor cells in vivo, can affect their estrogen responsiveness and may be an important mechanism underlying antiestrogen resistance in human breast cancer
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