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Cyr61, a Member of the CCN Family, Is Required for MCF-7 Cell Proliferation: Regulation by 17ß-Estradiol and Overexpression in Human Breast Cancer

Women’s Health Research Institute, Division of Endocrinology, Wyeth-Ayerst Research, Inc., Radnor, Pennsylvania 19087

Address all correspondence and requests for reprints to: Deepak Sampath, Ph.D., or Zhiming Zhang, Ph.D., Wyeth-Ayerst Research, Inc., 145 King of Prussia Road, Radnor, Pennsylvania 19087. E-mail: sampatd@war.wyeth.com or zhangz{at}war.wyeth.com

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 17ß-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 (ER) in a dose-dependent and immediate early fashion. Cyr61 gene induction by E₂ is transcriptionally regulated by ER 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.