Mary Helen Barcellos-Hoff, PhD

MARY HELEN BARCELLOS-HOFFProfessor of Radiation Oncology and Cell Biology
Ph.D., 1986 University of California, San Francisco

566 First Ave
8th Floor, Room 819
Rusk Research
New York, NY 10016
Tel: (212) 263-3021
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Research Theme(s): Identify the mechanisms of radiation effects on cell phenotype and tissue composition, e.g. stem cell regulation and epithelial-mesenchymal transition
Keywords: Ionizing Radiation, Radiation Carcinogenesis, High LET Radiobiology, Mammary Biology, Breast Cancer, Transforming Growth Factor β Biology, Radiotherapy Modifiers

Research Summary:

Cell function in complex three-dimensional tissues is coordinated by soluble signaling peptides and by small molecules within the context of insoluble scaffolding provided by the extracellular matrix. Cell interactions can actively suppress malignant behavior by epithelial cells, but atypical interactions can become active participants in carcinogenesis. My research goal is to better understand how tissues integrate information across multiple scales of organization and to use this information in modeling critical events in carcinogenesis using in vivo and in vitro models. 

A major focus of my laboratory is to study the multiple and complex mechanisms by which transforming growth factor b1 (TGFb) regulates epithelial function physiologically, the response to ionizing radiation (IR), and the consequences of its function during carcinogenesis. We discovered that TGFb is a prominent player in the response to IR, which in turn has revealed new aspects of its biology. TGFb1 is essential for epithelial cells to mount the canonical DNA damage response (Ewan et al., 2002a).  Irradiated Tgfb1 null murine epithelial cells fail to undergo cell cycle arrest or apoptosis in response to irradiation in vivo. Cell culture experiments demonstrate that this response is due to regulation of ATM kinase activity, can be phenocopied using small molecule TGFβ inhibitors in human epithelial cells, and can be reversed by TGFb1addition (Kirshner et al., 2006). Furthermore, TGFb and IR have a profound effect on epithelial phenotype, centrosome regulation and genomic stability (Andarawewa et al., 2009; Maxwell et al., 2008). A direct and specific requirement for TGFb in the genotoxic stress program provides a vital link between cell fate and tissue integrity. The dynamic interaction between target cells and the various cellular constituents of tissues is a novel target for therapeutics (Erickson and Barcellos-Hoff, 2003).

In normal mammary gland, TGFb specifically inhibits the proliferative potential of mammary epithelial cells in response to ovarian steroids. TGFb immunolocalization revealed striking epithelial heterogeneity during mammary stages characterized by proliferation (Ewan et al.). We found that TGFb1-positive and steroid hormone receptor co-localize in an epithelial subpopulation and that TGFb depletion specifically affects proliferation of hormone receptor positive cells (Ewan et al., 2005). A key approach of the lab has been quantitative image analysis to map location, morphology and effects (Parvin et al., 2003). We have used a novel image analysis strategy called ‘multiscale in situ sorting’ to study the regulation of stem cells in vivo (Fernandez-Gonzalez et al., 2009).

Ionizing radiation (IR), a prototypic carcinogen, rapidly and persistently alters tissue interactions (Barcellos-Hoff et al., 2005). The challenge in predicting radiation health effects in humans is to understand how cellular responses occurring in a multicellular context are integrated to produce an organismal response (Barcellos-Hoff, 2005). Identifying when and how tissue alterations contribute to the action of IR as a carcinogen may provide a means to inhibiting its carcinogenic potential, as well as a better understanding of how normal tissues suppress carcinogenesis. Ionizing radiation is one of a few demonstrable human breast carcinogens. The prevailing view is that radiation induces cancer through DNA damage, but this is inconsistent with many experimental studies showing that ionizing radiation evokes acute and persistent, short and long range, effects. The challenge remains to demonstrate that non-targeted radiation effects from doses relevant to human populations contribute to carcinogenesis.

We established a radiation chimera model in which the mammary gland is cleared of endogenous epithelium before the mouse is irradiated and subsequently transplanted with unirradiated, non-malignant epithelial cells (Barcellos-Hoff and Ravani, 2000). Mice that were irradiated with a high dose (400 cGy) and transplanted up to two weeks later with unirradiated, immortalized mammary epithelial cells, develop aggressive tumors even though normal outgrowths form in non-irradiated hosts. In recent studies, we use the radiation chimera to assess the frequency, rate and characteristics of carcinogenesis from a donor epithelium primed to undergo neoplastic transformation by genetic loss of p53. Carcinogenesis in Tp53 null tissue is similar to human breast cancer in that tumors exhibit genomic instability, differential expression of estrogen receptor, and heterogeneous histology and progress in situ from normal ductal outgrowths to ductal carcinoma in situ to invasive breast carcinomas. We found that tumor development was accelerated by host irradiation (Nguyen et al., 2011). Moreover these tumors were more aggressive and have molecular signatures distinct from tumors arising in non-irradiated hosts. Molecular and genetic approaches show that TGFβ mediated tumor acceleration. Tumor molecular signatures implicated TGFβ and genetically reducing TGFβ abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGFβ independent and linked to mammary stem cell activity. Thus the irradiated microenvironment affects latency and clinically relevant features of cancer through distinct and unexpected mechanisms.

Selected Publications: