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Breast cancer progression and metastasis have been linked to abnormal signalingby transforming growth factor-β (TGF-β) cytokines. In early-stage breast cancers,TGF-β exhibits tumor suppressor activity by repressing cell proliferation andinducing cell death, whereas in advanced-stage tumors, TGF-β promotes invasionand metastatic dissemination. The molecular mechanisms underlying pro-oncogenicactivities of TGF-β are not fully understood. The present study validates therole of TGF-β signaling in cancer progression and explores mediators of pro-oncogenicTGF-β activities using the LM3 mammary adenocarcinoma cell line, derived froma spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-βreceptors decreased both basal and TGF-β-induced invasion. Analysis of signaltransduction mediators showed that p38MAPK and MEK contribute to TGF-β stimulationof cell motility and invasion. TGF-β disrupted the epithelial actin structuressupporting cell-cell adhesions, and increased linear actin filaments. Moreover,MEK and p38MAPK pathways showed opposite effects on actin remodeling in responseto TGF-β. Blockade of Raf-MEK signaling enhanced TGF-β induction of actin stress-fiberswhereas p38MAPK inhibitors blocked this effect. A novel observation was made thatTGF-β rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-βstimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway.Experiments using syngeneic mice showed that kinase-inactive TGF-β receptors inhibitthe first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrineTGF-β signaling contributes to the invasive behavior of mammary carcinoma cells.Moreover, we show that both MAPK-dependent and -independent pathways are necessaryfor TGF-β-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potentialvenues for therapeutic intervention in pro-oncogenic TGF-β signaling.

TGF-β autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression