Last Updated: 5/17/2009

Research Interests
Human carcinomas show great diversity in their morphologies, clinical histories and in their responsiveness to therapy. This wide tumor diversity poses the main challenge to the effective treatment of cancer patients. The focus of my lab is to characterize the biological diversity of human tumors using genomics, genetics, and cell biology, and then to use this information to develop improved regimens that are specific for each tumor subtype. Our genomic characterization of human breast tumors identified at least six biologically distinct subtypes including Luminal A, Luminal B, Basal-like, HER2-enriched, Claudin-low and Normal-like (Hu et al. 2006, Herschkowitz et al. 2007, Parker et al. 2009); these Intrinsic Subtypes are predictive of relapse-free and overall survival times, and predictive of responsiveness to chemotherapy (Carey et al. 2007, Hugh et al. 2009, Parker et al. 2009). In addition to breast carcinomas we are also studying Head and Neck Squamous Cell Carcinomas (Chung et al. 2004), Lung Carcinomas (Hayes et al., 2006), Glioblastomas (TCGA, 2009) and Ovarian Carcinomas.

Concurrent with our tumor profiling studies are animal model and cell line projects that are aimed at determining the molecular function of the genes that define the Intrinsic Subtypes (Usary et al. 2004, Moyana et al. 2006, Thorner et al. 2009). As an example, my lab has shown that GATA3 is somatically mutated in some ER-positive breast tumors (Usary et al. 2004). The conditional knock-out of GATA3 in mouse mammary tissue greatly inhibited mammary gland development and caused a complete loss of luminal/ER+ epithelial cell formation. We have also determined that there are human germline variants of GATA3 that predispose to developing breast tumors (Garcia-Closas et al., 2007).

Although numerous mouse models of human breast carcinomas have been developed, we do not know the extent to which any faithfully represent clinically significant human tumor phenotypes. To address this need, we characterized mammary tumors from over 20 different murine models using DNA microarrays and identified many similarities to human breast tumors including proliferation and Intrinsic Subtype signatures (Herschkowitz et al., 2007). Our mouse modeling studies are an ongoing project where we are focused on further "humanizing" existing models, and then we use these models to empirically test new therapeutics in the preclinical setting; these preclinical mouse testing studies are being done through the UNC Mouse Phase I Unit, which is headed by myself, Dr. Ned Sharpless, and Dr. Bill Zamboni.

Our studies also depend upon computational biologists and the utilization of many bioinformatics tools. In addition to maintaining the UNC Microarray Database (https://genome.unc.edu/), our Lineberger Comprehensive Cancer Center Bioinformatics Group develops tools for the analysis of microarray data including Distance Weighted Discrimination (Benito et al. 2004) and LAS (Shabalin et al. 2009). DWD has allowed us to combine microarray data sets together from different groups or organisms, and to use the combined data to validate the prognostic and/or predictive importance of a given gene set (Hu et al. 2006, Herschkowitz et al., 2007). In summary, my lab utilizes a multi-disciplinary approach to characterize tumor diversity, we then use this information to understand more about tumor biology, and ultimately we design and run new clinical trials for cancer patients that are based upon our preclinical results. We are actively seeking new graduate students, medical fellows and postdocs and have opportunities available that utilize genomics, genetics, molecular and cellular biology, computational biology and human population genetics.

Publications
L.A. Carey, E.C. Dees, L. Sawyer, L. Gatti, D.T. Moore, F. Collichio, D.W.Ollila, C.I. Sartor, M.L. Graham, and C.M. Perou. The triple-negative paradox: Primary tumor chemosensitivity of breast cancer subtypes, Clinical Cancer Research, 13(8): 2329-2334, (2007). PMID: 17438091

J.I. Herschkowitz, K. Simin, V.J. Weigman, I. Mikaelian, J. Usary, Z. Hu, K.E. Rasmussen, L.P. Jones, S. Assefnia, S. Chandrasekharan, M. G. Backlund, Y. Yin, A.I. Khramtsov, R.I. Glazer, P.H. Brown, J.E. Green, L. Kopelovich, P.A. Furth, J.P. Palazzo, O.I. Olopade, P.S. Bernard, G.A. Churchill, T. Van Dyke, and C.M. Perou. Identification of conserved gene expression features across human and murine mammary tumors, Genome Biology, May 10;8(5):R76 [Epub ahead of print] (2007). PMID: 17493263

K.A. Hoadley, V.J. Weigman, C. Fan, L.R. Sawyer, X. He2, M.A. Troester, C.I. Sartor, T. Rieger-House, P.S. Bernard, L.A. Carey, and C.M. Perou. EGFR signaling varies with breast tumor subtype, BMC Genomics, Jul 31;8(1):258 [Epub ahead of print] (2007). PMID: 17663798

M. Garcia-Closas, M.A. Troester, Y. Qi, A. Langerd, M. Yeager, J. Lissowska, L. Brinton, R. Welch, B. Peplonska, D.S. Gerhard, I.T. Gram, V. Kristensen, A-L. Brresen-Dale, S. Chanock, and C.M. Perou. Common genetic variation in GATA3 and differential susceptibility to breast cancer by ER tumor status, Cancer Epidemiology, Biomarkers & Prevention, Nov;16(11):2269-2275 (2007). PMID: 18006915

Z. Li, C.E. Tognon, F.J. Godinho, L. Yasaitis, H. Hock, J.I. Herschkowitz, C.L. Lannon, E. Cho, S.-J. Kim, R.T. Bronson, C.M. Perou, P.H. Sorensen, and S.H. Orkin. ETV6-NTRK3 fusion oncogene initiates breast cancer from committed alveolar progenitors via activation of AP1 complex, Cancer Cell, 12: 542-558 (2007). PMID: 18068631

D.C. Allred, Y. Wu, S. Mao, I.D. Nagtegaal, S. Lee, Charles M. Perou, S.K. Mohsin, P. O'Connell, A. Tsimelzon and D. Mediana. Ductal Carcinoma In Situ and the Emergence of Diversity during Breast Cancer Evolution, Clinical Cancer Research, 14, 370-378 (2008). PMID: 18223211

M.C.U. Cheang, D. Voduc, C. Bajdik, S. Leung, S. McKinney, S. K. Chia, C.M. Perou, and T.O. Nielsen. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple negative phenotype, Clinical Cancer Research, 14(5) 1368-76 (2008). PMID: 18316557

A. Shabalin, H. Tjelmeland, C. Fan, C.M. Perou and A. Nobel. Merging Two Gene Expression Studies via Cross Platform Normalization, Bioinformatics, March 5th, (2008). PMID: 18325927

P.K. Julka, R.T. Chacko, S. Nag, R. Parshad, A. Nair, D.S. Oh, Z. Hu, C.B. Koppiker, S. Nair, R. Dawar, N. Dhindsa, I.D. Miller, D. Ma, B. Lin, B. Awasthy, and C.M. Perou. A Phase II Study of Sequential Neoadjuvant Gemcitabine Plus Doxorubicin Followed by Gemcitabine Plus Cisplatin in Patients with Operable Breast Cancer: Prediction of Response Using Molecular Profiling, British Journal of Cancer, Apr22;98(8), 1327-35 (2008). PMID: 18382427

L.A. Brown, J. Hoog, S.F. Chin, Y. Tao, A.A. Zayed, K. Chin, A.E. Teschendorff, J.F. Quackenbush, J.C. Marioni, S. Leung, C.M. Perou, T.O. Neilsen, M. Ellis, J.W. Gray, P.S. Bernard, D.G. Huntsman, and C. Caldas. ESR1 gene amplification in breast cancer: a common phenomenon? Nature Genetics Jul;40(7):806-7 (2008). PMID: 18583964

Cancer Genome Atlas (TCGA) Research Network, Comprehensive genomic characterization defines novel cancer genes and core pathways in human glioblastomas, Nature, Oct 23;455(7216):1061-8. (2008). PMID: 18772890

J.I. Herschkowitz, X. He, C. Fan and C.M. Perou. The functional loss of the retinoblastoma tumor suppressor is a common event in Basal-like and Luminal B breast cancers. Breast Cancer Research, 2008 Sep 9;10(5):R75. (2008). PMID: 18782450

B.P. Schneider, E.P. Winer, W.D. Foulkes, J. Garber, C.M. Perou, A. Richardson, G.W. Sledge and L.A. Carey. Triple negative breast cancer: risk factors to potential targets, Clinical Cancer Research, Dec 15;14(24):8010-8 (2008). PMID: 19088017

A.R. Thorner, K.A. Hoadley, J.S. Parker, S. Winkel, R.C. Millikan and C.M. Perou. In Vitro and In Vivo Analysis of B-MYB in Basal-like Breast Cancer. Oncogene, Feb 5;28(5):742-51. (2009). PMID: 19043454

J. S Parker, M. Mullins, M.C.U Cheang, S. Leung, D. Voduc, T. Vickery, X. He, Z. Hu, J.F Quackenbush, I.J. Stijleman, S. Davies, C. Fauron, J. Palazzo, J.S. Marron, A.B. Nobel, E. Mardis, T.O. Nielsen, M.J. Ellis, C.M. Perou, and P.S. Bernard. A supervised risk predictor of breast cancer based on intrinsic subtypes. Journal of Clinical Oncology, Mar 10;27(8):1160-7. (2009). PMID: 19204204

J. Hugh, J. Hanson, M. Cheang, T.O. Nielsen, C.M. Perou, C. Dumontet, J. Reed, M. Krajewska, I. Treilleux, M. Rupin, E. Magherini, J. Mackey, M. Martin, and C. Vogel. Breast Cancer Subtypes and Response to Docetaxel in Node-Positive Breast Cancer: Use of an immunohistochemical definition in the BCIRG 001 trial. Journal of Clinical Oncology, Mar 10;27(8):1168-76. (2009). PMID: 19204205

Z. Hu, C. Fan, C. Livasy, X. He, D.S. Oh, M.G. Ewend, L.A. Carey, S. Subramanian, R. West, F. Ikpatt, O.I. Olopade, M. van de Rijn and C.M. Perou. A compact VEGF signature associated with distant metastases and poor outcomes, BMC Medicine, Mar 16;7(1):9. (2009). PMID: 19291283

R. J. Crowder, C. Phommaly, Y. Tao, J. Hoog, R. Luo, C.M. Perou, J. Parker, M. Miller, D.G. Huntsman, L. Lin, J. Snider, S.R. Davies, J. Olson, M.A. Watson, A. Saporita, J.D. Weber and M.J. Ellis. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor positive breast cancer, Cancer Research, 69: (9). May 1, (2009). PMID: 19366795

M.C.U. Cheang, S.K. Chia, D. Voduc, D. Gao, S. Leung, P.S. Bernard, J. Parker, C.M. Perou, M.J. Ellis, and T.O. Nielsen. Ki-67 index, HER2 status, and prognosis in patients with Luminal B breast cancer. Journal of the National Cancer Institute, May 12. [Epub ahead of print] (2009). PMID: 19436038

X-H. Pei, F. Bai, M.D. Smith, J. Usary, C. Fan, I-C. Ho, C.M. Perou and Y. Xiong. p18Ink4c is a downstream target of GATA3 and restrains mammary luminal progenitor cell proliferation and tumorigenesis, Cancer Cell, May 5;15(5):389-401.(2009). PMID: 19411068

B.T. Hennessey, A.M. Gonzalez-Angulo, K. Hale, M.Z. Gilcrease, S. Krishnamurthy, J-S. Lee, J. Fridyland, A. Sahin, C. Joy, W. Liu, D. Stivers, K. Baggerly, M. Carey, A. Lluch, C. Monteagudo, X. He, V. Weigman, C. Fan, J. Palazzo, G.N. Hortobagyi, L.K. Nolden, N.J. Wang, V. Valero, J.W. Gray, C.M. Perou, and G.B. Mills. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Research, May 12. [Epub ahead of print] (2009). PMID: 19435916

D. Huo, F.Ikpatt, A. Khramtsov, J.-M. Dangou, R. Nanda, J. Dignam, B. Zhang, T. Grushko, C. Shang, O. Oluwasola, D. Malaka, R. Ndoma-Egba, S. Malami, A. Odetunde, A.O. Adeoye, F. Iyare, O. Adelusola, A. Falusi, C.M. Perou and O.I. Olopade. Population Differences in Breast Cancer: Survey in Indigenous African Women Reveal Overrepresentation of Triple Negative Breast Cancer. Journal of Clinical Oncology, In Press (2009).

A. Shabalin, V.J. Weigman, C.M. Perou and A.B. Nobel. Finding Large Average Submatrices in High Dimensional Data, Annals of Applied Statistics, In Press (2009).

E-mail: cperou@med.unc.edu
Telephone: (919) 843-5740
FAX: (919) 843-5718
Address: Lineberger Comprehensive Cancer Center, CB# 7295 Chapel Hill, NC 27599
URL: //peroulab.med.unc.edu/

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