Mary Helen Barcellos-Hoff, PhD

Professor; Departments of Radiation Oncology and Cell Biology

RESEARCH THEMES:
Cell Biology, Radiation Oncology

 

 

 

 

 

 

Contact Information

450 East 29th Street
Alexandria Building
Floor 3, Room 321
New York, NY 10016

Tel: 212-263-3021
EMail: mhbarcellos-hoff@nyumc.org

Action of radiation as a carcinogen in breast and as a cancer therapy in brain, breast and lung cancer

My laboratory studies ionizing radiation as both a carcinogen and cancer therapy. Ionizing radiation is a very relevant cancer risk factor. The use of radiation in diagnostic and therapeutic medical applications over the last 20 years has doubled the annual dose to the American public. Understanding the biological mechanisms underlying radiogenic cancer is important to identify who is at risk and to develop strategies to prevent harm. Of particular concern is that 50,000 women in the United States have been treated with chest radiation for a pediatric or young adult cancer. Preventing cancer is an unmet need in children and young people treated with radiation.

The focus of our project is to understand how the timing of radiation exposure affects the risk of developing breast cancer (Barcellos-Hoff, 2013a; Barcellos-Hoff, 2013b). Epidemiology underscores a common theme of greater risk when women are exposed at a young age even when there are substantial differences in total exposure dose, fractionation or volume. Exposure to ionizing radiation in utero does not increase breast cancer, exposure as a child confers a 3-fold increase in breast cancer risk, and radiation treatment for breast cancer increases relative risk by only 1.2. As yet unexplained is that a woman who is treated for childhood cancer with radiation has a very high risk of specifically developing aggressive, undifferentiated breast cancer before 40.

Radiation is a complete carcinogen that both initiates and promotes cancer. We use various approaches in mouse models and human cell cultures to investigate the contribution of different signals and events that affect cancer risk. We developed a murine mammary model that separates promotion from initiation, in which the irradiated mice are transplanted with unirradiated, oncogenically primed mammary cells (Barcellos-Hoff and Ravani, 2000). We found that this radiation chimera preferentially develops aggressive, basal-like mammary tumors (Nguyen et al., 2011), similar to those that occur in women treated with radiation for childhood cancers. Adult tissue stem cells are thought to be highly susceptible to neoplastic transformation and to give rise to undifferentiated, and often, more aggressive cancers. Microarray data from tumors arising in irradiated mice exhibit a strong mammary stem cell signature that is also found in aggressive human breast cancers (Nguyen et al., 2013). Our published data show the stem cell signature is evident in irradiated mammary gland long before tumors develop, and that functional stem cells increase when juvenile mice are irradiated. An inflammatory gene signature is also evident in irradiated mammary gland well before cancer develops, which is consistent with the idea that chronic, low grade inflammation promotes neoplastic progression. We hypothesize that radiation exposure during puberty induces a window of susceptibility by increasing the pool of transformed cells and inducing chronic inflammation that creates the critical context for malignant progression. Our data points to transforming growth factor β, TGFβ, as a key signal. Understanding how cancer occurs following radiation exposure will also afford insight into spontaneous events that promote sporadic cancer.