Effect of Conditional Knockout of the Type II TGF-β Receptor Gene in Mammary Epithelia on Mammary Gland Development and Polyomavirus Middle T Antigen Induced Tumor Formation and Metastasis

Abstract

Transforming growth factor-B (TGF-B) isoforms are growth factors that function physiologically to regulate development, cellular proliferation, and immune responses. The role of TGF-B signaling in mammary tumorigenesis is complex, as TGF-B has been reported to function as both a tumor suppressor and tumor promoter. To elucidate the role of TGF-B signaling in mammary gland development, tumorigenesis, and metastasis, the gene encoding type II TGF-B receptor, Tgfbr2, was conditionally deleted in the mammary epithelium (Tgfbr2

Tumor–stromal interactions reciprocally modulate gene expression patterns during carcinogenesis and metastasis

“…Recently, convincing evidence of interactions between individual genes or categories of genes (e.g., enzymes) in neoplastic and nonneoplastic cells within tumors has appeared in some reports. 16,[36][37][38][39][40] Moreover, Creighton et al 41 conducted global gene expression analysis and showed a network of tumor-stromal molecular interactions in a primary tumor xenograft model of lung cancer. Our current report now provides specific evidence that, during metastasis, labeled cancer cells and neighboring host cell lineages of 3 different organs (breast, lung and lymph node), reproducibly and reciprocally alter the expression of multiple groups of genes coordinately, upon encountering each other and/or the intercellular materials that they produce.…”

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.…”

“…However, experiments in mice reveal that TGFb is not a universal proliferation regulator; rather TGFb elicits its antiproliferative effects in specific contexts. For example, tissue-specific inactivation of TGFBR2 in mouse models rarely leads to spontaneous tumor formation with little to no pathology in mouse mammary epithelium, oral cavity esophagus, forestomach, pancreas, intestine, and skin [35][36][37][38][39]. Instead, TGFb's potent anti-proliferative effects only become apparent under conditions of tissue injury or oncogenic stress.…”

“…In cases of oncogenic stress, multiple examples demonstrate that deletions of TGFBR2 and SMAD4 strongly accelerate the malignant progression of cancerous lesions. Indeed, TGFBR2 deletion favors carcinomaformation in intestinal polyps initiated by APC inactivation or chemical mutagenesis [39,41], mammary tumors initiated by polyoma middle T (PyMT) expression [35], and pancreatic lesions initiated by KRAS [37]. Conversely, the expression of a constitutively activated TGFBR1 in the context of ErB2/HER2-driven mammary tumors results in delayed tumor formation and smaller tumor size [42,43].…”

Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression

“…During pregnancy, there is a three-fold increase in apoptosis in ductal and alveolar cells from Tgfb1 heterozygote compared to wild-type (WT) mouse mammary glands (Ewan et al, 2002). Postpubertal mice in which Tgfbr2 was conditionally deleted in the mammary gland also exhibit a much higher rate of apoptosis compared to controls (Forrester et al, 2005). Reports using cancer cells and/or transgenic mammary tumors further support a role for TGFb in the suppression of apoptosis (Huang et al, 2000;Muraoka et al, 2003).…”