Transforming Growth Factor–β Regulates Mammary Carcinoma Cell Survival and Interaction with the Adjacent Microenvironment

Abstract

Transforming growth factor (TGF)-B signaling has been associated with early tumor suppression and late tumor progression; however, many of the mechanisms that mediate these processes are not known. Using Cre/LoxP technology, with the whey acidic protein promoter driving transgenic expression of Cre recombinase (WAP-Cre), we have now ablated the type II TGF-B receptor (TBRII) expression specifically within mouse mammary alveolar progenitors. Transgenic expression of the polyoma virus middle T antigen, under control of the mouse mammary tumor virus enhancer/ promoter, was used to produce mammary tumors in the absence or presence of Cre (TBRII ( fl/fl);PY and TBRII ( fl/fl);PY;WC , respectively). The loss of TGF-B signaling significantly decreased tumor latency and increased the rate of pulmonary metastasis. The loss of TGF-B signaling was significantly correlated with increased tumor size and enhanced carcinoma cell survival. In addition, we observed significant differences in stromal fibrovascular abundance and composition accompanied by increased recruitment of F4/80 + cell populations in TBRII ( fl/fl);PY;WC mice when compared with TBRII ( fl/fl);PY controls. The recruitment of F4/80 + cells correlated with increased expression of known inflammatory genes including Cxcl1, Cxcl5, and Ptgs2 (cyclooxygenase-2). Notably, we also identified an enriched K5 + dNp63 + cell population in primary TBRII ( fl/fl);PY;WC tumors and corresponding pulmonary metastases, suggesting that loss of TGF-B signaling in this subset of carcinoma cells can contribute to metastasis. Together, our current results indicate that loss of TGF-B signaling in mammary alveolar progenitors may affect tumor initiation, progression, and metastasis through regulation of both intrinsic cell signaling and adjacent stromal-epithelial interactions in vivo.

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

“…GATA3 siRNA knockdown in T47D luminal breast cancer cells resulted in increased expression of a number of previously reported basal/myoepithelial markers including FOXC2, p-cadherin and CXCL1 (Rasbridge et al, 1993;Mani et al, 2007;Bierie et al, 2008) (Figure 5b (i)). Conversely, exogenous GATA3 expression in basal-like SUM149 cells resulted in downregulation of these same markers (Figure 5b (ii)).…”

Roles of TGFβ in metastasis

“…Indeed, knockout of TGFBR2 in the fibroblasts of the tumor microenvironment resulted in upregulation of HGF, MSP, TGF-a, and other secreted factors that significantly en-98 npg hanced the adjacent epithelial cells to proliferate [5,96]. Surprisingly, these studies show that TGFBR2 knockout animals developed significantly more pulmonary metastases compared with control mice [35,[97][98][99]. In a recent report, researchers have shown that targeted deletion of TGFBR2 in mouse mammary epithelium initiates the recruitment of myeloid immune suppressor cells through the CXCL5 axis.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…The increase in intra-tumor neutrophil number observed following anti-TGFβ signaling therapy can be explained by the ability of TGFβ to inhibit endothelial adhesiveness of neutrophils and neutrophil transmigration in vivo [91]. Abrogation of TGFβ signaling in mammary carcinomas also led to increased infiltration of Gr-1 + CD11b + MDSCs into the invasive front of tumor tissues facilitating tumor cell invasion and metastasis through a process involving metalloproteinase activity [82,92]. Interestingly, MDSCs from TGFβ signaling deficient tumor-bearing hosts produced higher levels of VEGF, MMP-2, MMP-13 and MMP-14 than those isolated from normal mice [82].…”