Functional interaction of fibroblast growth factor-8, bone morphogenetic protein and estrogen receptor in breast cancer cell proliferation

Mol Cell Endocrinol. 2011 Aug 22;343(1-2):7-17. doi: 10.1016/j.mce.2011.05.037. Epub 2011 Jun 1.


Estrogen is involved in the development and progression of breast cancer. Here we investigated the effect of fibroblast growth factor (FGF)-8 on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptor (ER)α, ERβ, FGF receptors, and Smad signaling molecules. Estradiol stimulated MCF-7 cell proliferation in a concentration-responsive manner, whereas BSA-bound estradiol had a weak effect on MCF-7 cell mitosis compared with the effect of free estradiol. It is notable that estrogen-induced cell proliferation was enhanced in the presence of FGF-8 and that the combined effects were reversed in the presence of an FGF-receptor kinase inhibitor or an ER antagonist. It was also revealed that FGF-8 increased the expression levels of ERα, ERβ and aromatase mRNAs, while estradiol reduced the expression levels of ERs, aromatase and steroid sulfatase in MCF-7 cells. FGF-8-induced phosphorylation of FGF receptors was augmented by estradiol, which was reversed by an ER antagonist. FGF-8-induced activation of MAPKs and AKT signaling was also upregulated in the presence of estrogen. On the other hand, FGF-8 suppressed BMP-7 actions that are linked to mitotic inhibition by activating the cell cycle regulator cdc2. FGF-8 was revealed to inhibit BMP receptor actions including Id-1 promoter activity and Smad1/5/8 phosphorylation by suppressing expression of BMP type-II receptors and by increasing expression of inhibitory Smads. Collectively, the results indicate that FGF-8 acts to facilitate cell proliferation by upregulating endogenous estrogenic actions as well as by suppressing BMP receptor signaling in ER-expressing breast cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aromatase / genetics
  • Aromatase / metabolism
  • Bone Morphogenetic Protein Receptors / genetics
  • Bone Morphogenetic Protein Receptors / metabolism
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor / drug effects*
  • Cell Proliferation*
  • Estradiol / pharmacology
  • Female
  • Fibroblast Growth Factor 8 / pharmacology*
  • Humans
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism
  • Steryl-Sulfatase / genetics
  • Steryl-Sulfatase / metabolism


  • Bone Morphogenetic Proteins
  • Receptors, Estrogen
  • Receptors, Fibroblast Growth Factor
  • Smad Proteins
  • Fibroblast Growth Factor 8
  • Estradiol
  • Aromatase
  • Bone Morphogenetic Protein Receptors
  • Steryl-Sulfatase