Abstract 1406: Tgfbr1 haploinsufficiency is a potent modifier of breast cancer risk

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.1406-1406
• Main Authors: Pennison, Michael J., Rosman-Balzer, Diana S., Moore-Smith, Lakisha, Zimmerman, Jacquelyn W., Schoeb, Trenton R., Frost, Andra R., Zhang, Ming, Siegel, Peter M., Pasche, Boris C.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-1406

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