Rachel Hazan, PhD

2012-2013 BCRF Project:
The First Step Award, made possible by generous support from QVC and the Fashion Footwear Charitable Foundation
Co-Investigator: Larry Norton, MD, Memorial Sloan-Kettering Cancer Center, New York, NY

Drs. Rachel Hazan and Larry Norton’s project focuses on the N-cadherin molecule, which is often found to be hyperactive in aggressive breast cancers. N-cadherin in breast cancers, driven by the Her2/neu oncogene, causes tumor cells to become more metastatic. Drs. Hazan and Norton observed in the laboratory that this molecule stimulates the spread of cancer cells  -- a finding that implies the targeting of N-cadherin might prevent the spread of tumor cells, and new therapies could be developed. Since relatively little is known about N-cadherin and its functions, this team set out to delineate the exact mechanisms of N-cadherin action on breast cancer metastasis. Their ultimate aim is to turn that information into new clinical strategies for metastasis prevention.

Drs. Hazan and Norton began their research with the hypothesis that N-cadherin promotes metastasis at two levels, by increasing the invasiveness of tumor cells and by providing access to blood vessels, which serve as an energy source fueling cancer growth. They sought to demonstrate in the laboratory setting that each mechanism depends on a different part of the N-cadherin protein and to map out key biological processes leading to malignant progression. Drs. Hazan and Norton have now collected evidence suggesting that N-cadherin can not only change a benign tumor cell into an aggressive one capable of healthy tissue invasion by activating critical metastatic cellular pathways but may also be a possible cause for resistance to the widely-used drug, Herceptin® (trastuzumab).

In 2012-2013, Drs. Hazan and Norton will continue to characterize the effects of N-cadherin on ErbB2/ErbB3 signaling, which is found to be hyper-activated in a subtype of breast cancer called HER2 positive disease, for which the targeted therapies Herceptin® (trastuzumab) and Tykerb® (lapatinib) were developed. This team's data to date suggest that N-cadherin may trigger resistance to this type of therapy. They will compare cell lines that have shown to be resistant to either Herceptin or Tykerb and determine whether these cell lines differ in their N-cadherin expression. The researchers will also test whether inhibiting the functions of N-cadherin would make these two targeted therapies effective again.

Mid-year Progress: Drs. Hazan and Norton's team found that a subset of breast cancers expresses N-cadherin and the FGF receptor (FGFR) in the context of HER2/neu. This causes tumor cells to behave like cancer stem cells and produce more metastatic cells. The researchers have found that FGFR inhibition is effective in attenuating HER2 positive metastatic tumors, but they predict that the combination of an FGFR inhibitor together with an HER2 inhibitor, such as lapatinib or trastuzumab, would more efficacious in subsiding aggressive breast tumors. Their study will continue to focus on these aspects of HER2 tumor biology.

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.