Joan S. Brugge, PhD

2012-2013 BCRF Project:
(made possible by generous support from Bloomingdale's)

Dr. Brugge's laboratory is investigating cellular processes that are involved in cancer progression. In one project, these researchers are investigating the mechanisms involved in the conversion of tumors from a non-invasive to invasive state. They have identified actin cytoskeletal regulators that act in concert to suppress invasion. They found that the EVL protein is a significant predictor of tumor grade and patient outcome, independent of ER, PR or HER2. A second project involves studies of the YAP1 gene, which is altered in human cancers and causes oncogenic transformation in cultured breast epithelial cells. Dr. Brugge's team has discovered a previously unrecognized function for this gene in regulating the final step in cell division, cytokinesis, and has elucidated key steps in this event that are regulated by YAP. A third project involves studies of a protein, PDEF, which is one of the most commonly upregulated genes in human breast tumors. These researchers have found that this gene regulates the differentiation of normal breast tumor epithelial cells and the downregulation of this gene in tumor cells alters their growth behavior and their differentiated state. In their fourth project, Dr. Brugge's team aims to identify stem/progenitor populations in the mammary gland. This study is based on the team's previous discovery of the potential link between pregnancy and a subset of progenitor cells in cancer formation.

In the coming year, Dr. Brugge's team will continue to investigate the mechanisms involved in the conversion from a noninvasive breast tumor to an invasive breast tumor. They will focus on studies of an invasion suppressor protein that is lost in high-grade tumors and a predictor or poor outcome as well expanding their analysis to understand more generally how alterations in the organization of the cellular cytoskeleton affect tumor behavior. They will also continue to study the protein YAP which has both tumor suppressor and tumor promoting functions and will focus on understanding the mechanism whereby this protein controls cell division.

In yet another project, Dr. Brugge's team plans to characterize the early adaptive responses that are induced following targeted therapy in HER2-positive (HER2+) tumors and test hypothesis-driven combinatorial strategies to improve the efficacy of treatment of patients with HER2+ tumors. While therapies that target specific molecular alterations in human tumors are showing significant efficacy in the clinic, drug resistance remains a major obstacle. Studies from Dr. Brugge's laboratory and others have independently provided evidence that PI3K- and HER2- targeted therapies induce a program of molecular responses to drug treatment that significantly contributes to drug resistance. Dr. Brugge's team has additional evidence that the nature and levels of compensatory pathway activation and associated drug resistance is strongly influenced by the local microenvironment-in particular, basement membrane/extracellular matrix (BM/ECM). Importantly, they have found that inhibition of key components of the adaptive response, like BCL-2, abrogates the drug-induced adaptive resistance. These studies indicate that adaptive responses can rescue cancer cells from the inhibitory effects of the targeted therapies, thus promoting drug resistance. Variations in the adaptive responses among tumors preclude a uniform combinatorial approach to therapy. In the upcoming year, Dr. Brugge's team plans to characterize the early adaptive responses that are induced following targeted therapy in HER2-positive tumors and test hypothesis-driven combinatorial strategies to improve the efficacy of treatment of patients with HER2+ tumors.

Mid-year Progress: Continuing their work on the process of transition from a non-invasive breast tumor to invasive breast cancer, Dr. Brugge's team completed studies of a complex of proteins that suppress tumor cell invasion and published a report in Cancer Cell describing how this complex functions and how changes in the expression of complex components can provoke more aggressive invasive behavior in human tumors. They also found that this protein is a significant predictor of poor outcome in human breast cancer patients. In another project in collaboration with BCRF grantee, Myles Brown, MD (Dana-Farber Cancer Institute), they identified the functional activities of a protein, PDEF, which is one of the most highly expressed protein in ER-positive breast cancers. These studies show the PDEF can drive differentiation of breast cells and that it is critical for survival of ER+ breast tumor cells.

In their study of combinatorial approaches to prevent early adaptive responses to HER2- and PI3K-targeted therapies in breast cancer, Dr. Brugge's team has initiated studies designed to define adaptive responses to targeted treatments for breast cancer. These adaptive responses can significantly decrease the sensitivity of the tumor cells to the targeted therapies and allow maintenance of drug resistant cell populations. The team's previous studies identified specific niches within the tumor that specifically undergo these responses. During the first few months of funding, they have generated DCIS-like and invasive tumors from HER2+ human tumor cell lines in laboratory models treated with a HER2 specific drug. The treated and control laboratory models will be analyzed in the coming months to define responses in different tumor contexts for distinct populations of tumor cells.

Bio:
Joan Brugge joined the faculty of the Department of Cell Biology at Harvard Medical School in July 1997 and became the Chair of this department in 2004. A graduate of Northwestern University, she did her graduate work at the Baylor College of Medicine, completing her PhD in 1975. During her postdoctoral training at the University of Colorado she isolated the protein coded for the viral and cellular forms of the src gene. These proteins were the first viral/cellular oncogene products to be identified, and the study of the normal and oncogenic forms of this gene product has served as a model system to investigate cellular processes that regulate normal growth and the mechanisms involved in tumor formation.

In the 15 years since that discovery, Dr. Brugge has held full professorships at the State University of New York, Stony Brook, and the University of Pennsylvania, where she was also named as an investigator at the Howard Hughes Medical Institute. In 1992 Dr. Brugge left academia to help found a new company, ARIAD, to focus on research aimed at developing new drugs for asthma and allergy, cystic fibrosis, cancer, and other diseases that result from cellular regulation gone awry.

Dr. Brugge has received several awards recognizing her scientific accomplishments including an NIH Merit Award, an American Cancer Society Research Professorship and the Senior Career Recognition Award from the American Society of Cell Biology, and she has been elected to the American Academy of Arts and Sciences, the National Academy of Sciences and the Institute of Medicine.