title: Functional interaction of fibroblast growth factor-8, bone morphogenetic protein and estrogen receptor in breast cancer cell proliferation.
abstract: 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.
authors.affiliation: Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Masuda
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Mariko
authors.initials: M
authors.lastname: Takano
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Shien
authors.forename: Naruto
authors.initials: N
authors.lastname: Taira
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Doihara
mesh_terms: D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects*; D049109:Cell Proliferation; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000494:pharmacology*; D006801:Humans; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D043266:Steryl-Sulfatase / Q000235:genetics / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D011960:Receptors, Estrogen; D017468:Receptors, Fibroblast Growth Factor; D051785:Smad Proteins; D051524:Fibroblast Growth Factor 8; D004958:Estradiol; D001141:Aromatase; D052004:Bone Morphogenetic Protein Receptors; D043266:Steryl-Sulfatase