Cyr61, a member of the CCN family, is required for MCF-7 cell proliferation: regulation by 17beta-estradiol and overexpression in human breast cancer

Endocrinology. 2001 Jun;142(6):2540-8. doi: 10.1210/endo.142.6.8186.

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 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.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Antibodies / pharmacology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Cell Division*
  • Cysteine-Rich Protein 61
  • DNA, Neoplasm / biosynthesis
  • Dactinomycin / pharmacology
  • Epidermal Growth Factor / pharmacology
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology*
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha
  • Fulvestrant
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Growth Substances / genetics*
  • Growth Substances / immunology
  • Growth Substances / physiology
  • Humans
  • Immediate-Early Proteins / genetics*
  • Immediate-Early Proteins / immunology
  • Immediate-Early Proteins / physiology
  • In Situ Hybridization
  • Intercellular Signaling Peptides and Proteins*
  • RNA, Messenger / analysis
  • Receptors, Estrogen / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcriptional Activation
  • Tumor Cells, Cultured

Substances

  • Antibodies
  • CCN1 protein, human
  • Cysteine-Rich Protein 61
  • DNA, Neoplasm
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Growth Substances
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Receptors, Estrogen
  • Dactinomycin
  • Fulvestrant
  • Estradiol
  • Epidermal Growth Factor