Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis

Gal, A.; Sjoeblom, T.; Fedorova, L.; Imreh, S.; Beug, H.; Moustakas, A.

Oncogene 27(9): 1218-1230


ISSN/ISBN: 0950-9232
Accession: 021839638

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To better understand the dual, tumour-suppressive and tumour-promoting function of transforming growth factor-beta (TGF beta), we analysed mammary epithelial NMuMG cells in response to short and long-term TGFb exposure. NMuMG cells became proliferation-arrested and apoptotic after exposure to TGFb for 2-5 days, whereas surviving cells underwent epithelial-mesenchymal transition (EMT). After chronic TGFb exposure (2-3 weeks), however, NMuMG cells became resistant to proliferation arrest and apoptosis, showing sustained EMT instead (TD cells). EMT was fully reversed by a pharmacologic TGF beta-receptor-I kinase inhibitor or withdrawal of TGFb for 6-12 days. Interestingly, both cell cycle arresting/proapoptotic (Smads, p38 kinase) and antiapoptotic, proliferation and EMT-promoting signalling pathways (PI3K-PKB/Akt, ERK) were co-suppressed to low, but significant levels. Except for PI3K-Akt, TGF beta-dependent downregulation of these signalling pathways in transdifferentiated (TD) cells was fully reversed upon TGFb withdrawal, together with partial re-induction of proliferation arrest and apoptosis. Co-injection of non-tumorigenic NMuMG cells with tumour-forming CHO cells oversecreting exogenous TGF beta 1 (CHO-TGF beta 1) allowed outgrowth of epithelioid cells in CHO-TGF beta 1 cell-induced tumours. These epithelial islands enhanced CHO-TGF beta 1 tumour cell proliferation, possibly due to chemokines (for example, JE/MCP-1) secreted by NMuMG/TD cells. We conclude that suppression of antiproliferative, proapoptotic TGF beta signalling in TD cells may permit TGF beta-dependent proliferation, survival and EMT-enhancing signalling pathways to act at low levels. Thus, TGF beta may modulate its own signalling to facilitate switching from tumour suppression to tumour progression.