Dr. Barcellos-Hoff studies breast cancer, mammary biology, radiation carcinogenesis, and biological mechanisms to augment radiotherapy. Her laboratory has 2 broad objectives: One is to use mouse models to determine critical cell and tissue interactions that modulate mammary carcinogenesis and the spectrum of intrinsic subtypes in breast cancer.

The other is to identify targetable TGFβ biology in tumors and the tumor microenvironment that mediate response to therapy. Dr. Barcellos-Hoff received an undergraduate degree from the University of Chicago and earned a doctoral degree in experimental pathology from the University of California, San Francisco (UCSF).

She conducted postdoctoral research on extracellular matrix and functional differentiation at the Lawrence Berkeley National Laboratory, which she joined as a staff scientist in 1988 and rose to Senior Scientist and Associate Director of the Life Sciences Division before moving to the Department of Radiation Oncology of New York University School of Medicine in 2008. In 2015, she was appointed Professor and Vice Chair of Research in the Department of Radiation Oncology at UCSF.

ABSTRACT

Title: Transforming growth factor β: New tricks for an old fox
Mary Helen Barcellos-Hoff, Department of Radiation Oncology, University of California San Francisco

Summary: Repair of DNA damage protects genomic integrity and is key to tissue functional integrity. In cancer, the type and fidelity of DNA damage response is the fundamental basis for clinical response to cytotoxic therapy. Survival of head and neck squamous cell carcinoma (HNSCC) patients with human papilloma virus (HPV) positive cancer is more than double that of HPV-negative HNSCC.

Our studies demonstrate that signaling competency by transforming growth factor-beta (TGFβ), an abundant, pleotropic cytokine in the tumor microenvironment, mediates response DNA damage responses (doi: 10.1158/1078-0432.CCR-18-1346). HPV infection profoundly weakens TGFβ signaling, this loss of TGFβ signaling shifts cancer cells from error-free homologous-recombination DNA double-strand-break (DSB) repair to error-prone alternative end-joining (altEJ); notably, pharmaceutical TGFβ inhibition phenocopies HPV infection.

Cells using altEJ have more mutations, are more sensitive to standard of care radiotherapy and cisplatin, and are sensitized to PARP inhibitors. I will discuss the rationale for the use of TGFβ inhibitors for optimal therapeutic combinations to improve patient outcome.