Consequences of altered TGF-β expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects

Abstract

To characterize the impact of increased production of TGF-b in a xenograft model of human breast cancer, TGF-b-responsive MDA-231 cells were genetically modi®ed by stable transfection so as to increase their production of active TGF-b1. Compared with control cells, cells that produced increased amounts of TGF-b proliferated in vitro more slowly. In vivo, however, tumors derived from these cells exhibited increased proliferation and grew at an accelerated pace. To evaluate the role of autocrine TGF-b signaling, cells were also transfected with a dominant-negative truncated type II TGF-b receptor (TbRII). Disruption of autocrine TGF-b signaling in the TGF-b-overexpressing cells reduced their in vivo growth rate. Co-inoculation of Matrigel with the TGF-b-overexpressing cells expressing the truncated TbRII compensated for their diminished in vivo growth capacity, compared with the TGF-b-overexpressing cells with an intact autocrine loop. Tissue invasion by the tumor was a distinctive feature of the TGF-b-overexpressing cells, whether or not the autocrine loop was intact. Furthermore, tumors derived from TGFb-overexpressing cells, irrespective of the status of the autocrine TGF-b-signaling pathway, had a higher incidence of lung metastasis. Consistent with the suggestion that TGF-b's enhancement of invasion and metastasis is paracrine-based, we observed no signi®cant di erences among the cell clones in an in vitro invasion assay. Thus, in this experimental model system in vitro assays of cell proliferation and invasion do not accurately re¯ect in vivo observations, perhaps due to autocrine and paracrine e ects of TGF-b that in¯uence the important in vivo-based phenomena of tumor growth, invasion, and metastasis.

TGF-β1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival

“…Tobin et al, (2002) observed a marked enhancement of tumour growth in vivo by tumour-derived TGF-b when an autocrine loop was left intact. Studies also found that increased production of TGF-b1 by tumour cells was associated with potential invasiveness and metastasis of cancer (Gorsch et al, 1992;Dalal et al, 1993;Ueki et al, 1993;Tobin et al, 2002).…”

“…Studies of TGF-b1 signal transduction provided further evidence that low expression of TbRII by breast cancer cells was correlated with enhanced in vivo malignant behaviours both in tumour specimens and a cancer cell line (Gobbi et al, 1999). Tobin et al, (2002) observed a marked enhancement of tumour growth in vivo by tumour-derived TGF-b when an autocrine loop was left intact. Studies also found that increased production of TGF-b1 by tumour cells was associated with potential invasiveness and metastasis of cancer (Gorsch et al, 1992;Dalal et al, 1993;Ueki et al, 1993;Tobin et al, 2002).…”

The GH–IGF-I axis and breast cancer

“…These include tubulin alpha 3, which has been previously found to be overexpressed in malignant breast tumours immunohistochemically 160 Transforming growth factor beta 1, a multifunctional peptide that controls proliferation and differentiation, was also upregulated 2.15 fold in the IGF-1 positive tumours 161 . In addition it has been shown to promote the formation of lung metastases in animal models of breast cancer 161 . We also found an over expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM 1)…”

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

“…Overexpression of TGF-b was observed in tumors in association with metastasis (Kopp et al, 1995) or increased cell invasiveness (Tobin et al, 2002;Dumont et al, 2003). An important function related to promotion of metastasis is the phenomenon of EMT.…”