Abstract 1406: Tgfbr1 haploinsufficiency is a potent modifier of breast cancer risk.
Authors: Michael J. Pennison, Diana S. Rosman-Balzer, Lakisha Moore-Smith, Jacquelyn W. Zimmerman, Trenton R. Schoeb, Andra R. Frost, Ming Zhang, Peter M. Siegel, Boris C. Pasche
Journal: Cancer Research (2013)

Abstract Background: We previously identified a hypomorphic TGF-β type 1 receptor variant (TGFBR1*6A) that is associated with cancer risk and has impaired TGF-β signaling capability. Two recent large meta-analyses of case control studies have found a significant association between TGFBR1*6A and risk of several types of cancer, including breast cancer (ORs 1.16,1.01-1.34; 1.15,1.01-1.31). To investigate the effects of constitutively decreased TGFBR1 signaling on cancer development, we developed a novel mouse model of Tgfbr1 haploinsufficiency to mimic the decreased TGFBR1 signaling observed in individuals with higher risk of cancer. Using this model, we demonstrated that Apcmin;Tgfbr1+/- mice develop more than twice as many intestinal tumors as Apcmin controls. The aim of the current study was to assess the effects of Tgfbr1 haploinsufficiency on breast carcinogenesis by crossing Tgfbr1+/- mice with the MMTV-c-Neu mouse model. Methods: Fully congenic (100%) FVB/N-Tgfbr1+/- mice were crossed with FVB/N-Neu mice, and female virgin progeny were kept for analysis. Mammary glands were collected from 10, 12, and 40 week-old Neu and Neu;Tgfbr1+/- mice. Mice assessed for tumor development were sacrificed 80 days after the initial tumor palpation or at the earliest sign of morbidity. Whole lungs, tumor tissue, and primary tumor cells were collected for additional analysis. Long-term evaluation of 2-year-old Tgfbr1+/+ and Tgfbr1+/- mice was also conducted to directly assess the impact of Tgfbr1 haploinsufficiency on mammary gland and lung development. Results: Mammary gland whole mounts revealed that Neu;Tgfbr1+/- mice have more ductal branching at all time points compared to Neu mice. In the assessment of breast tumor development, Neu;Tgfbr1+/- mice were observed to have a significantly shorter tumor latency period (171 days) compared to Neu mice (220 days) (p=0.004). Seventy percent of Neu;Tgfbr1+/- mice (14/20) developed surface lung metastases, while 36.4% were observed in Neu mice (8/22), a borderline significant difference (p=0.061). The TGF-β-mediated growth inhibition of Neu;Tgfbr1+/- primary tumor cells was 32.2% lower than that of Neu tumor cells (p=0.007). Neu;Tgfbr1+/- tumor cells and tissue had significantly reduced Smad2/3 phosphorylation and total Cdkn1b (p27Kip1) expression compared to Neu mice. Long-term evaluation of Tgfbr1+/- and wild-type mice revealed no signs of mammary gland hyperplasia or differences in lung fibrosis in either group. Conclusion: This study is the first in vivo evidence that Tgfbr1 haploinsufficiency promotes breast carcinogenesis by increasing breast cancer proliferation. The relevance of this data to human breast cancer warrants additional investigations into the effects of decreased TGFBR1 signaling on tumor development and progression and identifies potential targets for prevention and treatment. Citation Format: Michael J. Pennison, Diana S. Rosman-Balzer, Lakisha Moore-Smith, Jacquelyn W. Zimmerman, Trenton R. Schoeb, Andra R. Frost, Ming Zhang, Peter M. Siegel, Boris C. Pasche. Tgfbr1 haploinsufficiency is a potent modifier of breast cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1406. doi:10.1158/1538-7445.AM2013-1406 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.