Reciprocal interactions between luminal epithelial cells and their surrounding microenvironment regulate normal mammary gland development and function. One critical component of these interactions involves steroid hormone receptors, extracellular matrix (ECM) components, and ECM receptors, that ultimately generate an orchestrated functional control of steroid hormone responsiveness of the mammary gland. Alterations of these interactions can induce abnormal intracellular signaling pathways that affect the development and progression of breast tumors.

---

The relative levels and activities of the two estrogen receptor (ER) isoforms (ERa and ERb) may affect the normal development of the mammary gland, the etiology of hormone-dependent cancers, and the response to hormonal therapies. Our studies focused on ERa, in part because this isoform is indispensable for mammary growth and differentiation. To better understand how the intracellular signaling pathways function in normal cells and to identify how the same pathways become altered in tumor cells, we assessed ERa gene regulation by ECM in functionally normal and malignant mammary cell lines.
In a study using primary cultures of normal mammary epithelial cells, we found that the basement membrane (BM) molecules, laminin-1 and collagen-IV, allow appreciable maintenance of ERa expression, and that this response can be interfered with by disrupting cell-BM adhesion using specific integrin blocking antibodies (Novaro et al., 2003). By using a phenotypically normal established mammary epithelial cell line, Scp2, we are dissecting the promoter region of the ERa that is involved in the selective response to BM and its components. We found that the region for this response is localized between -5kb and -2.5 kb of the ERa promoter and contains consensus Stat5 and C/EBPb sites separated by 446 bp that may constitute a minimal enhancer. We observed that this same 5’-untranslated region of the mouse ERa promoter when introduced into ScG6 cells, a malignant cell line that shares a common lineage with Scp2 cells but overexpresses ERa, did not respond to BM. Thus, context-dependent regulation of ER activity appears to be a fundamental and specific property of non malignant mammary epithelial cells and it appears that ScG6, the malignant cell line used here, by-pass the regulatory effect of the BM on ERa expression. The study of the signaling pathways involved in the two mammary cell lines should help delineate how normal and malignant cells regulate ERa expression and function, and may shed some light on the alterations that lead to the initiation and progression to malignancy in the mammary gland.