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Cyr61, A Member Of The CCN Family, Is Required For MCF-7 Cell Proliferation: Regulation By 17β-Estradiol And Overexpression In Human Breast Cancer

Deepak Sampath, Richard C. Winneker, Zhiming Zhang

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Abstract Cyr61, a member of the CCN (CTGF/Cyr61/NOV) family of growth regulators, is a secreted cysteine-rich proangiogenic factor that has been implicated in tumorigenesis. Previous studies have also demonstrated that Cyr61 is regulated by 17β-estradiol (E2) in the uterus. Therefore, we hypothesized that hormonal regulation of Cyr61 may be important in estrogen-dependent pathogenic processes such as breast tumorigenesis. Our study demonstrates that both Cyr61 messenger RNA and protein are induced by E2 in MCF-7 mammary adenocarcinoma cells that primarily overexpress estrogen receptor α (ERα) in a dose-dependent and immediate early fashion. Cyr61 gene induction by E2 is transcriptionally regulated by ERα as the antiestrogen, ICI 182,780, and actinomycin D blocked induction completely. In addition, Cyr61 is up-regulated in MCF-7 cells by epidermal growth factor (EGF) in an immediate early fashion as well. The functional relevance of steroid induction of Cyr61 in breast cancer cell growth is demonstrated by anti-Cyr61 neutralizing antibodies, which diminished E2 and EGF-dependent DNA synthesis and dramatically reduced E2-driven cell proliferation by more than 70%. Most importantly, Cyr61 is overexpressed in 70% (28 of 40) of breast cancer patients with infiltrating ductal carcinoma and is localized exclusively to hyperplastic ductal epithelial cells. Moreover, the levels of Cyr61 protein are higher in breast tumors that are ER+/EGF receptor+ than those that are ER−/EGF receptor+, suggesting that estrogens may mediate Cyr61 expression in vivo. Collectively, our data suggest that Cyr61 may play a critical role in estrogen- as well as growth factor-dependent breast tumor growth.