The Role of TGF-beta Variants in Breast Cancer

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TGF-β has been named the molecular Jekyll and Hyde of cancer due to its ability to both suppress and promote tumor development. Components of the TGF-β signaling pathway are often mutated in cancer to inhibit the tumor suppressor roles of TGF-β. Our lab studies how a 3-alanine deletion in the signal sequence region of the type 1 TGF-β receptor (TGFBR1) increases cancer risk. This mutation, known as <em>TGFBR1</em>*6A, confers a 15% increased risk for breast cancer compared to individuals who carry two copies of the wildtype (*9A) receptor. There is a 40% increased risk for homozygosity. My thesis project was to investigate the effects of <em>TGFBR1</em>*6A on breast cancer development. TGF-β induces a 30% growth inhibitory response in MCF-7 breast cancer cells. However TGFBR1*6A expression conferred a TGF-β-mediated growth advantage to the cells. In addition, TGFBR1*6A enhanced the ability for MCF-7 cells to migrate and invade through a matrigel barrier independently of TGF-β. Microarray studies identified 2 crucial mediators of migration that are downregulated in MCF-7*6A cells compared to MCF-7*9A cells: <em>ARHGAP5</em>, the gene encoding the RhoGTPase activating protein 5, and <em>FN1</em>, the gene encoding Fibronectin-1. Downregulation of <em>ARHGAP5</em> led to increased activation of RhoA. TGFBR1*6A expression also amplified ERK activation. MCF-7 cells expressing kinase-deficient TGFBR1*6A exhibited TGF-β-mediated growth stimulation and decreased expression of <em>ARHGAP5</em> and <em>FN1</em>, indicating that the effects of *6A are mediated through its signal sequence and not through the canonical SMAD signaling. This is the first evidence that TGFBR1*6A can exert functions that are independent of TGF-β and that the effects of TGFBR1*6A are mediated through the signal sequence peptide and not through receptor activation. Our lab generated a novel <em>Tgfbr1</em> haploinsufficient mouse strain and observed that, when crossed with mouse models of colon cancer, there was a significantly increased frequency of colorectal tumors. Additionally, we have recently discovered that germline allele specific expression (ASE) of TGFBR1 increases the risk for human colorectal cancer. I therefore set out to determine if TGFBR1 haploinsufficiency would impact breast cancer development. This <em>Tgfbr1<sup>+/-</sup></em> mouse model was mated to the commonly used <em>MMTV-c-Neu</em> proto-oncogenic mouse model that spontaneously develops mammary tumors. <em>Neu;Tgfbr1<sup>+/-</sup></em> mice had a significant decrease in tumor latency compared to the <em>Neu</em> mice. There is some indication that <em>Tgfbr1<sup>+/-</sup></em> may enhance lung metastases in the <em>Neu</em> mouse model. This is the first evidence that <em>Tgfbr1<sup>+/-</sup></em> may enhance breast cancer development. >Alterations in the TGF-β signaling pathway are becoming increasingly common in breast cancer. My research has shown how two different variants of TGFBR1, TGFBR1*6A and haploinsufficiency of TGFBR1, have the potential to impact patient's risk for breast cancer and disease progression.

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  • 10/01/2018
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