Role of Stroma-Derived Extracellular Matrix in Regulation of Growth and Hormonal Responsiveness of Normal and Cancerous Human Breast Epithelium

摘要

Extra cellular matrix (ECM) proteins are critical for differentiation of normal mammary epithelial cells, but pronounced changes in ECM occurs during breast cancer. We have determined that estrogen receptor (ER)-positive breast cancer cells (MCF-7 and T47D) cultured on laminin have reduced, or lack, estrogen responses. Estrogen-induced proliferation was significantly reduced on LM but did occur on collagens, fibronectin, poly-L-lysine or vitronectin. laminin did not inhibit IGF-I or EGF induced proliferation, indicating that tumor cells on laminin do not become refractory to mitogens. An endogenous estrogen regulated protein; the progesterone receptor, was not significantly stimulated by estrogen on laminin, but was stimulated on collagen I or fibronectin, indicating that laminin may inhibit ER binding or post-receptor events. However, ER content, ER binding and expression of ER splice variants was not different in different ECM proteins. Estrogen stimulation of ERE transcription was down regulated in MCF-7 cells cultured on laminin. MCF-7 cells injected into nude mice grew 5 times slower when coinjected with LM in response to E (when compared to Col I coinjection), and did not respond to antiestrogens. These studies demonstrate that ECM proteins may regulate estrogen action and anti-estrogen action which are critical in secondary treatment for breast cancer.