Conditional Overexpression of Active Transforming Growth Factor β1 In vivo Accelerates Metastases of Transgenic Mammary Tumors

Abstract

To address the role of transforming growth factor (TGF) ␤ in the progression of established tumors while avoiding the confounding inhibitory effects of TGF-␤ on early transformation, we generated doxycycline (DOX)-inducible triple transgenic mice in which active TGF-␤1 expression could be conditionally regulated in mouse mammary tumor cells transformed by the polyomavirus middle T antigen. DOX-mediated induction of TGF-␤1 for as little as 2 weeks increased lung metastases >10-fold without a detectable effect on primary tumor cell proliferation or tumor size. DOX-induced active TGF-␤1 protein and nuclear Smad2 were restricted to cancer cells, suggesting a causal association between autocrine TGF-␤ and increased metastases. Antisense-mediated inhibition of TGF-␤1 in polyomavirus middle T antigen-expressing tumor cells also reduced basal cell motility, survival, anchorage-independent growth, tumorigenicity, and metastases. Therefore, induction and/or activation of TGF-␤ in hosts with established TGF-␤-responsive cancers can rapidly accelerate metastatic progression.

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

“…TGFb has been shown to activate PI3K and its target Akt (Higaki and Shimokado, 1999;Bakin et al, 2000;Yi et al, 2005). Although the signaling programs regulating TGFb-mediated protection from cell death are not completely understood, this protection is blocked by the PI3K inhibitor LY294002 and/or expression of dominantnegative Akt (Shin et al, 2001;Horowitz et al, 2004;Muraoka-Cook et al, 2004). These data are consistent with the ability of TGFb to behave as a tumor promoter in late phases of transformation (Wakefield and Roberts, 2002).…”

“…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). Conditional overexpression of active TGFb1 in a triple transgenic model expressing polyomavirus middle T antigen in the mammary gland (MMTV/PyVmT) inhibits apoptosis and accelerates metastases (Muraoka-Cook et al, 2004). In MMTV/ PyVmT transgenic mice, systemic administration of a soluble TbRII increases tumor cell apoptosis and reduces metastases (Muraoka et al, 2002a).…”

Molecular profiling of cervical cancer progression

“…Transforming growth factor (TGF)-b stimulates epithelialmesenchymal transition of SiHa cervical cancer cells, indicating a positive role in the invasive transition of cervical cancer (Yi et al, 2002). Although TGF-b is both a tumour suppressor and tumour promoter, TGF-b inhibitors are currently widely tested for the treatment of cancer (Muraoka-Cook et al, 2004;Elliott and Blobe, 2005;Lahn et al, 2005). Various genes were downregulated in LN micrometastases, such as major histocompatibility complex (MHC) class II antigens and NME1.…”

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

“…Recently, the progression and metastases of breast cancer in the transgenic mouse was shown to be driven by autocrine TGFb1 secretion, especially during the stage when epithelial breast cells are transforming into mesenchymal cell types. 78 While it is of interest that the tumor suppressor network can both accommodate growth suppression and the oncogenic role of Egr1, this hypothetical basis for an oncogenic role of Egr1 remains untested. The preponderance of experimental evidence, however, strongly indicates that in formed prostate carcinomas, Egr1 is oncogenic.…”