title: Estrogen and antiestrogens alter breast cancer invasiveness by modulating the transforming growth factor-β signaling pathway.
abstract: In the later stages of breast cancer, estrogen receptor (ER)α-negative cancers typically have higher histological grades than ERα-positive cancers, and transforming growth factor (TGF)-β promotes invasion and metastasis. Our previous study indicated that ERα inhibited TGF-β signaling by inducing the degradation of Smad in an estrogen-dependent manner. In the present study, we report that the suppressive effects of ERα and estrogen on tumor progression are mediated by inhibiting TGF-β signaling. Furthermore, we investigated the effects of antiestrogens such as ICI182,780 (ICI) or tamoxifen (TAM) on TGF-β signaling and breast cancer invasiveness. The levels of total Smad and pSmad were reduced by estrogen, whereas ICI slightly increased them, and TAM had no effect. To investigate the effect of antiestrogens on breast cancer invasiveness, we generated highly migratory and invasive MCF-7-M5 cells. The migration and invasion of these cells were suppressed by the inhibitor of TGF-β receptor kinase, SB-505124, and estrogen. However, antiestrogens did not suppress the migration and invasion of these cells. In addition, we screened TGF-β target genes whose expression was reduced by estrogen treatment and identified four genes associated with breast cancer invasiveness and poor prognosis. The expression of these genes was not decreased by antiestrogens. These observations provide a new insight into estrogen function and the mechanisms underlying estrogen-mediated suppression of tumor progression.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Natsuka
authors.initials: N
authors.lastname: Goto
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hiyoshi
authors.forename: Ichiaki
authors.initials: I
authors.lastname: Ito
authors.forename: Mai
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Junn
authors.initials: J
authors.lastname: Yanagisawa
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000502:physiology; D004967:Estrogens / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D015398:Signal Transduction; D051785:Smad Proteins / Q000032:analysis / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D051785:Smad Proteins; D016212:Transforming Growth Factor beta