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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Carrie R. Graveel, Ph.D. Breast Cancer Signaling and Therapeutics Dr. Graveel earned her Ph.D. in cellular and molecular biology from the University of Wisconsin–Madison in 2002. She then served as a postdoctoral fellow in the laboratory of George Vande Woude at VARI from 2002 to 2007. In 2007, she became a Research Scientist and in 2010 was promoted to Senior Research Scientist. Dr. Graveel is currently a Research Assistant Professor in VARI and an Instructor in the VAI Graduate School. From left: Linklater, Graveel, Essenburg Staff Curt Essenburg, B.S. Erik Linklater, B.S. Student Josh Castle 10

Graveel Research Interests Receptor tyrosine kinase signaling can promote the growth, invasion, and survival of both normal and cancerous cells. In cancer, altered receptor tyrosine kinases frequently drive tumor initiation, progression, and metastasis. Understanding how these receptors signal in breast cancer cells is crucial to developing successful therapeutic strategies. The goal of the team is to identify novel therapeutic targets and prognostic signatures of therapy resistance in breast cancer. Dr. Graveel is focused on the role of the MET receptor and the ERBB receptor family in breast cancer progression and therapy resistance. Triple-negative breast cancer (TNBC) accounts for 15–20% of breast cancers and generally has an advanced stage at diagnosis and a poorer outcome than other breast cancer subtypes. Tyrosine kinases are promising druggable targets due to their high expression in TNBC, but in the clinic, tyrosine kinase inhibitors have had limited success. Recent clinical studies of non-small-cell lung cancer (NSCLC) suggest that combined inhibition of MET and EGFR improves and prolongs therapeutic efficacy in a subset of patients. The goals of our research are to determine MET and EGFR expression, activation, and signaling in TNBC; to determine the efficacy of MET and EGFR inhibition on TNBC progression in vivo; and to identify unique molecular drivers of African-American and European-American TNBC. Numerous studies have demonstrated that paracrine interactions between breast cancer cells and the tumor microenvironment (including stromal fibroblasts and inflammatory cells) promote tumor progression and metastasis. To investigate how oncogenic signaling from the microenvironment influences the progression of TNBC, we are using the MET and IL-6 pathways as a paradigm of oncogenic/inflammatory interactions. In collaboration with Bonnie Sloane (Wayne State University) and Patricia LoRusso (Karmanos Cancer Institute), we are investigating MET and IL-6 inhibitors to determine whether combined inhibition of these pathways will be beneficial to TNBC patients. Our goals are to determine MET and IL-6 activation and signaling in TNBC; to investigate the effect of MET and/or IL-6 inhibition on TNBC cell invasion using 3D co-culture models; and to determine the efficacy of MET and IL-6 inhibition on TNBC progression and metastasis in vivo. Recent Publications Mackenzie, Todd A., Gary N. Schwartz, Heather M. Calderone, Carrie R. Graveel, Mary E. Winn, Galen Hostetter, Wendy A. Wells, and Lorenzo F. Sempere. In press. Stromal expression of miR-21 identifies high-risk group in triple-negative breast cancer. American Journal of Pathology. Graveel, Carrie R., David Tolbert, and George F. Vande Woude. 2013. MET: a critical player in tumorigenesis and therapeutic target. Cold Spring Harbor Perspectives in Biology 5(7): a009209. Paulson, Amanda K., Erik S. Linklater, Bree D. Berghuis, Colleen A. App, Leon D. Oostendorp, Jayne E. Paulson, Jane E. Pettinga, Marianne K. Melnik, George F. Vande Woude, and Carrie R. Graveel. 2013. MET and ERBB2 are coexpressed in ERBB2 + breast cancer and contribute to innate resistance. Molecular Cancer Research 11(9): 1112–1121. 11

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