Increased Malignancy of Neu-Induced Mammary Tumors Overexpressing Active Transforming Growth Factor β1

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Abstract
To determine if Neu is dominant over transforming growth factor β (TGF-β), we crossed mouse mammary tumor virus (MMTV)-Neu mice with MMTV-TGF-β1S223/225 mice expressing active TGF-β1 in the mammary gland. Bigenic (NT) and Neu-induced mammary tumors developed with a similar latency. The bigenic tumors and their metastases were less proliferative than those occurring in MMTV-Neu mice. However, NT tumors exhibited less apoptosis and were more locally invasive and of higher histological grade. NT mice exhibited more circulating tumor cells and lung metastases than Neu mice, while NT tumors contained higher levels of phosphorylated (active) Smad2, Akt, mitogen-activated protein kinase (MAPK), and p38, as well as vimentin content and Rac1 activity in situ than tumors expressing Neu alone. Ex vivo, NT cells exhibited higher levels of P-Akt and P-MAPK than Neu cells. These were inhibited by the TGF-β inhibitor-soluble TGF-β type II receptor (TβRII:Fc), suggesting they were activated by autocrine TGF-β. TGF-β stimulated migration of Neu cells into surrounding matrix, while the soluble TGF-β inhibitor abrogated motility and invasiveness of NT cells. These data suggest that (i) the antimitogenic and prometastatic effects of TGF-β can exist simultaneously and (ii) Neu does not abrogate TGF-β-mediated antiproliferative action but can synergize with TGF-β in accelerating metastatic tumor progression.