Laminin inhibits estrogen action in human breast cancer cells.
Breast tumors that lack estrogen responsiveness have a poor prognosis. Despite the critical importance to breast cancer treatment, little is known about the loss of estrogen responsiveness and the development of antiestrogen resistance. We have examined the regulation of estrogen-induced proliferation, estrogen regulation of progesterone receptor (PR) expression, and estrogen signaling pathways in estrogen receptor (ER) positive (MCF-7 and T47D) breast cancer cell lines by specific extracellular matrix proteins (ECM) under serum-free conditions. Estrogen, supplemented with submaximal concentrations of insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF), stimulated DNA synthesis of MCF-7 cells 7- to 10-fold and T47D cells 2-fold on collagen I or fibronectin. However, estrogen-induced proliferation was greatly reduced on laminin. In contrast, IGF-I or EGF, alone, stimulated proliferation of MCF-7 and T47D cells on all ECM. Thus, ER+ breast cancer cells were not refractory to mitogens when cultured on laminin. Similarly, estrogen induction of PR occurred on fibronectin or collagen I, but not on laminin. While ER content was similar on all ECM, estrogen stimulation of estrogen response element (ERE)-luciferase activity was significantly lower in MCF-7 cells cultured on laminin. Therefore, changes in ECM composition that occur in breast cancer may alter estrogen-responsiveness and the effectiveness of antiestrogen therapies in ER+ breast cancer cells.
Department of Physiology, Michigan State University, East Lansing 48824-1101, USA.
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Woodward
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Haslam
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D003470:Culture Media; D016895:Culture Media, Serum-Free; D004247:DNA / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007797:Laminin / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D003470:Culture Media; D016895:Culture Media, Serum-Free; D004965:Estrogen Antagonists; D004967:Estrogens; D016326:Extracellular Matrix Proteins; D007797:Laminin; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D004247:DNA