Cyr61, a member of the CCN family, is required for MCF-7 cell proliferation: regulation by 17beta-estradiol and overexpression in human breast cancer.
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 17beta-estradiol (E(2)) 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 E(2) in MCF-7 mammary adenocarcinoma cells that primarily overexpress estrogen receptor alpha (ERalpha) in a dose-dependent and immediate early fashion. Cyr61 gene induction by E(2) is transcriptionally regulated by ERalpha 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 E(2) and EGF-dependent DNA synthesis and dramatically reduced E(2)-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.
Sampath
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Women's Health Research Institute, Division of Endocrinology, Wyeth-Ayerst Research, Inc., Radnor, Pennsylvania 19087, USA. sampatd@war.wyeth.com
Winneker
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Zhang
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D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000906:Antibodies / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002455:Cell Division; D055515:Cysteine-Rich Protein 61; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003609:Dactinomycin / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006133:Growth Substances / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger / Q000032:analysis; D011960:Receptors, Estrogen / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D000906:Antibodies; C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D004273:DNA, Neoplasm; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D003609:Dactinomycin; D000077267:Fulvestrant; D004958:Estradiol; D004815:Epidermal Growth Factor