Dr. Graveel received her B.A. in chemistry from Kalamazoo College in 1996 and worked as a research associate at Pharmacia and Upjohn Inc. from 1996–1997. She then attended the University of Wisconsin-Madison where she received her Ph.D. in cellular and molecular biology in 2002. She performed her postdoctoral fellowship with Dr. George Vande Woude at VARI from 2002–2007 and was promoted to research scientist in 2007 and senior research scientist in 2010. Dr. Graveel then served as a research assistant professor in Dr. Vande Woude’s laboratory until 2016, when she accepted a position in the Steensma Laboratory.
Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancers and is associated with advanced stage at diagnosis and poorer outcome compared to other breast cancer subtypes. Treatment options for TNBC patients are restricted to chemotherapy; however tyrosine kinases are promising druggable targets due to their high expression in TNBC.
The success of trastuzumab in HER2+ breast cancer underscores the promise of targeting tyrosine kinases. In spite of this promising start, tyrosine kinase inhibitors (TKIs) have had limited success in the clinic. Both innate and acquired resistance are significant clinical issues for TKIs, in part due to compensation signaling through other kinases. Recent clinical studies in non-small cell lung cancer (NSCLC) suggest that combinatorial MET and EGFR inhibition improves and prolongs therapeutic efficacy in a subset of patients. While MET and EGFR are expressed in the majority of TNBCs, we have evidence that TNBC has de novo resistance to EGFR inhibition through MET activation and that MET and EGFR inhibition is effective in abrogating TNBC tumor progression. For clinical success to become a reality with TKI strategies, it is imperative that we understand the compensatory mechanisms by which tumors develop resistance. The goal of our research is:
Our studies combine a novel aggregate of innovative proteomic approaches, quantitative analysis of MET and EGFR expression and activation, and in vivo models of TNBC. With these approaches, we are investigating the unique molecular drivers of TNBC and will gain a significant understanding of the role of MET, EGFR, and additional signaling pathways in TNBC. Furthermore, we will identify proteomic signatures that will represent MET and/or EGFR activation and response to monotherapy or combined MET and EGFR inhibition. These studies will fill a critical gap in knowledge in TNBC network signaling and their effect on therapeutic response.
To view a list of selected publications click below.
Dischinger PS, Tovar EA, Essenburg CJ, Madaj ZB, Gardner EE, Callaghan ME, Turner AN, Challa AK, Kempston T, Eagleson B, Kesterson RA, Bronson RT, Bowman MJ, Graveel CR, Steensma MR. 2018. NF1 deficiency correlates with estrogen receptor signaling and diminished survival in breast cancer. npj Breast Cancer 4.
Peacock JD, Pridgeon MG, Tovar EA, Essenburg CJ, Bowman M, Madaj Z, Koeman J, Boguslawski EA, Grit J, Dodd RD, Khachaturov V, Cardona DM, Chen M, Kirsch DG, Maina F, Dono R, Winn ME, Graveel CR, Steensma MR. 2018. Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors. Cancer Res 78(13):3672–3687.
Sameni M, Tovar EA, Essenburg C, Chalasani A, Linklater ES, Borgman A, Cherba DM, Anbalagan A, Winn ME, Graveel CR, Sloane BF. 2016. Cabozantinib (XL184) inhibits growth and invasion of preclinical TNBC models. Clin Cancer Res 22(4):923–934.
Paulson AK, Linklater ES, Berghuis BD, App CA, Oostendorp LD, Paulson JE, Pettinga JE, Melnik MK, Vande Woude GF, Graveel CR. 2013. MET and ERBB2 are coexpressed in ERBB2+ breast cancers and contribute to innate resistance. Mol Cancer Res11(9):1112–1121.
Graveel CR, Tolbert D, Vande Woude GF. 2013. MET: A critical player in tumorigenesis and therapeutic target. Cold Spring Harb Perspect Biol, eds Schlessinger J & Lemmon MA (Cold Spring Harbor).
Valkenburg KC, Graveel CR, Zylstra-Diegel CR, Zhong Z, Williams BO. 2011. Wnt/β-catenin signaling in normal and cancer stem cells. Cancers 3(2):2050–2079.
Graveel CR, DeGroot JD, Sigler RE, Vande Woude GF. 2010. Germline Met mutations in mice reveal mutation- and background-associated differences in tumor profiles. PLoS One 5(10):e13586.
Graveel CR, DeGroot JD, Su Y, Koeman J, Dykema K, Leung S, Snider J, Davies SR, Swiatek PJ, Cottingham S, Watson MA, Ellis MJ, Sigler ME, Furge KA, Vande Woude GF. 2009. Met induces diverse breast carcinomas in mice and is associated with human basal breast cancer. Proc Natl Acad Scis U S A 106:12909–12914.
Graveel CR, London CA, Vande Woude GF. 2005. A mouse model of activating Met mutations. Cell Cycle 4:518–520.
Graveel CR, Su Y, Koeman J, Wang LM, Tessarollo L, Fiscella M, Birchmeier C, Swiatek P, Bronson R, Vande Woude GF. 2004. Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele. Proc Natl Acad Sci U S A 49:17198–17203.
Graveel CR, Harkins-Perry SR, Acevedo LG, Farnham PJ. 2003. Identification and characterization of CRG-L2, a new marker for liver tumor development. Oncogene 22(11):1730–1736.
*Wells J, *Graveel CR, Bartley SM, Farnham PJ. 2002. The identification of E2F1-specific target genes. Proc Natl Acad Sci U S A 99(6):3890–3895.
*Authors contributed equally
Graveel CR, Jatkoe T, Madore SJ, Holt AL, Farnham PJ. 2001. Expression profiling and identification of novel genes in hepatocellular carcinomas. Oncogene 20(21):2701–2712.
Lukas ER, Bartley SM, Graveel CR, Diaz ZM, Dyson N, Harlow E, Yamasaki L, Farnham PJ. 1999. No effect of loss of E2F1 on liver regeneration or hepatocarcinogenesis in C57BL/6J or C3H/HeJ mice. Mol Carcinog 25:295–303.
18 Oct. 2017 Breast Cancer Awareness Month: A look at the latest research
Ilan Tsarfaty, Ph.D. —Tel Aviv University
Julie Boerner, Ph.D.—Wayne State University
Bonnie Sloane, Ph.D. —Wayne State University
E. Chip Petricoin, Ph.D. —George Mason University
Beatrice Knudsen, M.D., Ph.D. —Cedars-Sinai
Arkaduisz Gertych Ph.D. —Cedars-Sinai
Marianne Melnik, M.D. —Spectrum Health
Melinda Miller, M.D. —Spectrum Health
Colleen App, M.D. —Spectrum Health
Leon Oosterndorp, M.D. —Spectrum Health
Jayne Paulson, M.D. —Spectrum Health
Jane Pettinga, M.D. —Spectrum Health