Mary Helen Barcellos-Hoff, PhD

Understanding the action of TGFβ in irradiated tissues and cells led us to define its role in genomic instability and a previously understudied role in the DNA damage response.  This led us to test whether TGFβ inhibition improve the response to radiotherapy, which substantiated its critical role in the irradiate tumor. 

1. Bouquet, S.F., A. Pal, K.A. Pilones, S. Demaria, B. Hann, R.J. Akhurst, J.S. Babb, S.M. Lonning, J.K. DeWyngaert, S. Formenti, and M.H. Barcellos-Hoff. 2011. Transforming growth factor β1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res. 17:6754-6765. PMID: 22028490
2. Hardee, M.E., A.E. Marciscano, C.M. Medina-Ramirez, D. Zagzag, A. Narayana, S.M. Lonning, and M.H. Barcellos-Hoff. 2012. Resistance of Glioblastoma-Initiating Cells to Radiation Mediated by the Tumor Microenvironment Can Be Abolished by Inhibiting Transforming Growth Factor-β. Cancer Res. 72 (16):4119-29. PMC3724539  
3. Kirshner, J., M.F. Jobling, M.J. Pajares, S.A. Ravani, A. Glick, M. Lavin, S. Koslov, Y. Shiloh, and M.H. Barcellos-Hoff. 2006. Inhibition of TGFb1 signaling attenuates ATM activity in response to genotoxic stress. Cancer Res. 66:10861-10868. PMID: 17090522
4. Maxwell, C.A., M.C. Fleisch, S.V. Costes, A.C. Erickson, A. Boissiere, R. Gupta, S.A. Ravani, B. Parvin, and M.H. Barcellos-Hoff. 2008. Targeted and non-targeted effects of ionizing radiation that impact genomic instability. Cancer Res. 68:8304-8311. PMID:18922902

Radiation carcinogenesis is classically understood in terms of DNA damage and the potential increase in oncogenic mutations.  Based on our studies showing that radiation alters critical signaling and cell-cell interactions, we developed a radiation chimera mammary model that unequivocally demonstrates that radiation effects on the microenvironment strongly promote carcinogenesis.  Remarkably, the expression data from tumors arising in irradiated mice can be used to cluster cancers from irradiated humans and supports the contention that this mechanism of action contributes to radiation-preceded cancer in humans and that similar processes may underlie the origin of sporadic human cancers.

1. Barcellos-Hoff, M.H., and S.A. Ravani. 2000. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res. 60:1254-1260. PMID:10728684
2. Nguyen, D.H., H.A. Oketch-Rabah, I. Illa-Bochaca, F.C. Geyer, J.S. Reis-Filho, J.H. Mao, S.A. Ravani, J. Zavadil, A.D. Borowsky, D.J. Jerry, K.A. Dunphy, J.H. Seo, S. Haslam, D. Medina, and M.H. Barcellos-Hoff. 2011. Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type. Cancer Cell. 19:640-651. PMC3110779
3. Nguyen, D.H., E. Fredlund, W. Zhao, C.M. Perou, A. Balmain, J.-H. Mao, and M.H. Barcellos-Hoff. 2013. Murine Microenvironment Metaprofiles Associate with Human Cancer Etiology and Intrinsic Subtypes. Clin Cancer Res. 19:1353-1362.  PMC3732211
4. Zhang, P., Lo, A., Huang, Y., Huang, G., Liang, G., Mott, J., Karpen, G.H., Blakely, E.A., Bissell, M.J. Barcellos-Hoff, M.H., Snijders, A.M., Mao, J.H.  Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment. Sci Rep. 2015 Mar 9;5:8919. PMC4352890