Rachel Hazan, PhD

2007-2008 BCRF Project:
The First Step Award, made possible by generous support from the Fashion Footwear Charitable Foundation and QVC
Co-Investigator: Larry Norton, MD, Memorial Sloan-Kettering Cancer Center, New York, NY

Aggressive breast cancers abnormally express the cell-cell adhesion molecule N-cadherin, and Drs. Hazan and Norton and colleagues showed that this expression stimulates metastasis with no effects on primary tumors. This relationship implies that targeted therapies aimed at N-cadherin might eradicate metastasizing tumor cells and be useful at a clinically intractable stage. Since their c-neu model is a reliable model of metastasizing breast cancer, the researchers will use it to delineate the exact mechanism of N-cadherin action on metastasis. They hypothesize N-cadherin promotes metastasis at two levels, by increasing the invasiveness of tumor cells (signaling), and by localizing tumor cells to blood vessels (adhesion). Their studies will first demonstrate that each mechanism depends on a different part of the N-cadherin protein, and then examine new drugs that selectively target these distinct N-cadherin functions. The researchers believe that the information gained will have important clinical implications for treatment of late-stage breast cancer.

Mid-Year Progress Report:
Aggressive breast cancers abnormally express the cell-cell adhesion molecule N cadherin. N-cadherin in breast cancers driven by the Her2/neu oncogene causes tumor cells to become more metastatic. Dr. Hazan, along with Dr. Norton and her team, performed a thorough in vivo characterization of the c-neu-N-cadherin model for metastasis to map out key biological phenotypes leading to malignant progression. Their most recent studies show that N-cadherin accelerates the induction of breast neoplasms, enhances angiogenesis and activates lung metastasis. The researchers will continue to investigate the causal relationship between N-cadherin and breast cancer metastasis in order to gain novel insights into targeted therapies to eradicate metastasis.

Bio:
Dr. Rachel Hazan received her PhD from George Washington University in 1990. She accomplished her thesis work in the laboratory of Dr. Joseph Schlessinger where she studied the role of Her2/neu signal transduction in breast cancer. During this work, she characterized the tyrosine phosphorylation sites on Her2/neu and generated a panel of monoclonal antibodies against HER2/neu which were successful in suppressing breast cancer cell growth and transformation.

She then joined the laboratory of Dr. Gerald Edelman at Rockfeller University and Scripps Research Institute as a postdoctoral fellow to learn about adhesion molecules which were just beginning to be implicated in cancer progression. This background served as a basis for her current work in which she is investigating how cadherin adhesion molecules and growth factor receptors cooperate in tumor metastasis.

In 1994, she joined the department of Surgery at Memorial Sloan-Kettering Cancer Center as an Assistant Laboratory Member and initiated work on the role of adhesion molecules in breast cancer. In 1997, she joined Mount-Sinai School of Medicine as an Assistant Professor and in 2003 the Albert Einstein College of Medicine as Associate Professor of Pathology.

Dr. Hazan found that a neural cadherin, N-cadherin was overexpressed in most invasive and metastatic human breast cancer cell lines and tumors. N-cadherin induces metastasis due to its ability to bind and potentiate signaling by the FGF receptor. She is currently pursuing the genes and downstream signaling pathways that are promoted by the N-cadherin-FGFR axis as well as how N-cadherin adhesive interactions with the host microenvironment also play a role in tumor dissemination. Her current studies involve the use of transgenic breast cancer mouse models in which mammary co-expression of N-cadherin with the PyVmT antigen or the Her2/neu oncogene were found to dramatically increase the metastatic potential of breast cancer cells. These models will serve as a basis to determine the molecular mechanisms underlying N-cadherin metastatic activity and identify targets for translational or therapeutic application in breast cancer.