scholarly journals Semaphorin-7a reverses the ERF-induced inhibition of EMT in Ras-dependent mouse mammary epithelial cells

2012 ◽  
Vol 23 (19) ◽  
pp. 3873-3881 ◽  
Author(s):  
Maryline Allegra ◽  
Andreas Zaragkoulias ◽  
Elena Vorgia ◽  
Marina Ioannou ◽  
Gabriele Litos ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Ras Signaling ◽  
Collagen Gels ◽  
Mesenchymal Transition ◽  
Oncogenic Ras

Epithelial-to-mesenchymal transition (EMT) is a key process in cancer progression and metastasis, requiring cooperation of the epidermal growth factor/Ras with the transforming growth factor-β (TGF-β) signaling pathway in a multistep process. The molecular mechanisms by which Ras signaling contributes to EMT, however, remain elusive to a large extent. We therefore examined the transcriptional repressor Ets2-repressor factor (ERF)—a bona fide Ras–extracellular signal-regulated kinase/mitogen-activated protein kinase effector—for its ability to interfere with TGF-β–induced EMT in mammary epithelial cells (EpH4) expressing oncogenic Ras (EpRas). ERF-overexpressing EpRas cells failed to undergo TGF-β–induced EMT, formed three-dimensional tubular structures in collagen gels, and retained expression of epithelial markers. Transcriptome analysis indicated that TGF-β signaling through Smads was mostly unaffected, and ERF suppressed the TGF-β–induced EMT via Semaphorin-7a repression. Forced expression of Semaphorin-7a in ERF-overexpressing EpRas cells reestablished their ability to undergo EMT. In contrast, inhibition of Semaphorin-7a in the parental EpRas cells inhibited their ability to undergo TGF-β–induced EMT. Our data suggest that oncogenic Ras may play an additional role in EMT via the ERF, regulating Semaphorin-7a and providing a new interconnection between the Ras- and the TGF-β–signaling pathways.

Actions of the soy phytoestrogen genistein in models of human chronic disease: potential involvement of transforming growth factor β

2001 ◽  
Vol 29 (2) ◽  
pp. 216-222 ◽  
Author(s):  
H. Kim ◽  
J. Xu ◽  
Y. Su ◽  
H. Xia ◽  
L. Li ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Mammary Epithelial Cells ◽  
Hormone Replacement ◽  
Transforming Growth Factor Β ◽  
Mammary Epithelial ◽  
Primate Model ◽  
Human Mammary Epithelial Cells ◽  
Human Mammary Epithelial

The structural similarity, but non-identity, between 17β-oestradiol and the soy phytoestrogen genistein suggests that the two compounds will have actions that may be identical in some target biological systems, but different in others. Epidermal growth factor (EGF)-stimulated proliferation of human mammary epithelial cells (that do not express the oestrogen receptor) was significantly suppressed at genistein concentrations (5–10μM) that are attainable physiologically. Others have shown previously that transforming growth factor β (TGFβ) has similar growth-inhibitory effects on human cells. Analysis of the conditioned medium of human mammary epithelial cells exposed to genistein plus EGF showed increased levels of TGFβ relative to those in the medium of cells exposed to EGF or genistein alone. Related experiments in a primate model of menopause demonstrated that ingestion of soy containing isoflavones was correlated with the suppression of neurodegeneration-relevant phosphorylation of the microtubule-associated protein tau, while intake of Premarin (a hormone replacement therapy that is commonly prescribed for women) was not correlated. The results discussed here indicate that genistein, and probably other related phytoestrogens, have pleiotropic actions, some of which may involve TGFβ activity.

Sign in / Sign up

Export Citation Format

Share Document