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Molecular and Cellular Biology - Rosen Lab

Houston, Texas

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Rosen Lab
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Jason Herschkowitz, Ph.D.

Jason Herschkowitz, Ph.D.

Project Description

I am interested in cancer stem cells or tumor initiating cells (TIC) in breast cancer. Evidence has shown that these cells may have an intrinsic resistance to radiation and chemotherapeutics compared to the bulk of the tumor. These cells also may be responsible for metastatic dissemination and tumor dormancy and recurrence. Therefore, it is important to understand the biology of TIC in order to develop targeted therapies to eradicate these cells.

Evidence from our laboratory and others has shown that there exist cells within tumors that have an intrinsic resistance to radiation and chemotherapeutics compared to the bulk of the tumor. These cells referred to as cancer stem cells (CSC) or tumor-initiating cells also may be responsible for metastatic dissemination and tumor dormancy and recurrence. Therefore, it is important to understand the biology of CSCs in order to develop targeted therapies to eradicate these cells.

Over the last three years, I have been studying a molecular subtype of breast cancer I first identified during my graduate studies. Genomic profiling of human breast tumors has classified them into several distinct and clinically relevant groups (basal-like, luminal A, luminal B, HER2-enriched, and normal-like). We identified a rare molecular subtype of human breast cancer that we refer to as the claudin-low group. Like basal-like tumors, these tumors are generally triple negative (ER-, PR-, HER2-), however they uniquely express low levels of tight and adherens junction genes including Claudin 3 and E-cadherin. Claudin-low tumors also often highly express markers associated with epithelial to mesenchymal transition (EMT) and a core EMT pathway signature.

We have also been able to show that a signature we derived from human CSCs is both enriched post-treatment and also in the claudin-low subtype. Through comparative genomics, we previously discovered that there are mouse mammary tumors that have similar gene expression characteristics as claudin-low human tumors. Tumors in this group were rare tumors that came from a number of distinct mouse models including the p53 null transplant model. We have now collected more tumors from the p53 null model and patient derived xenografts in order to identify claudin-low tumors that we can transplant and expand in vivo with the goal of using this tumor bank for mechanistic and preclinical studies. Using the gene expression and copy number data we have accumulated, we will choose genes (with a focus on non-coding RNAs) and pathways (including an EMT network) to inhibit with lentiviral shRNAs in claudin-low tumors. By perturbing these pathways, we hope to sensitize claudin-low tumors and CSCs in general to conventional therapies.

Overall, my goal is to understand the biology of breast CSCs that will enable the development of targeted therapeutic strategies to eliminate them.

  • Joined Lab: September 2007
  • Position: Postdoctoral Fellow
  • Degrees: BA, SUNY Buffalo, 1998, MFS, George Washington University, 2000 & Ph.D. UNC-Chapel Hill, 2008.
  • Awards: Susan G. Komen Foundation Postdoctoral Fellowship (2007-2010)

Publications

Giulianelli S, Herschkowitz JI, Patel V, Lamb CA, Gutkind JS, Molinolo A, Perou CM, and Lanari C. MPA-induced gene expression and stromal and parenchymal gene expression profiles in luminal murine mammary carcinomas with different hormonal requirements. Breast Cancer Res Treat. 2010 Oct 2. [Epub ahead of print] PMID: 20890655

Prat A, Parker JS, Fan C, Karginova O, Livasy C, Herschkowitz JI, He X, and Perou CM.. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010 Sep 2;12(5):R68. [Epub ahead of print] PMID: 20813035

Jiang Z, Deng T, Jones R, Li H, Herschkowitz JI, Liu JC, Weigman VJ, Tsao M, Lane T, Perou CM, and Zacksenhaus E. Rb deletion in mouse mammary progenitors induces luminal-B or basal-like/EMT tumor subtypes depending on p53 status. J Clin Invest. 2010 Aug 2. pii: 41490. doi: 10.1172/JCI41490. [Epub ahead of print] PMID: 20679727

Greene SB, Herschkowitz JI, and Rosen JM. Small Players With Big Roles: microRNAs As Targets To Inhibit Breast Cancer Progression. Curr Drug Targets. 2010 Jun 14. [Epub ahead of print] PMID: 20545613

Taube J, Herschkowitz JI, Kakajan K, Zhou A, Gupta S, Yang J, Hartwell K, Onder T, Gupta P, Evans KW, Hollier BG, Ram P, Lander E, Rosen JM, Weinberg RA and Mani SA. A core EMT interactome gene expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15449-54. Epub 2010 Aug 16. PMID: 20713713

Herschkowitz JI. Breast cancer stem cells: initiating a new sort of thinking. Dis Model Mech. 2010 May-Jun;3(5-6):257-8. PMID: 20427552

Greene SB, Herschkowitz JI, and Rosen JM. The ups and downs of miR-205: Identifying the roles of miR-205 in mammary gland development and breast cancer. RNA Biol. 2010 May 21;7(3). [Epub ahead of print] PMID: 20436283

Pond AC, Herschkowitz JI, Schwertfeger KL, Welm B, Zhang Y, York B, Cardiff RD, Hilsenbeck S, Perou CM, Creighton CJ, Lloyd RE, and Rosen JM. FGFR signaling enhances mammary tumorigenesis through translational mechanisms. Cancer Res. 2010 Jun 15;70(12):4868-79. Epub 2010 May 25. PMID: 20501844

Creighton C, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, Rimm DL, Wong H, Rodriguez A, Herschkowitz JI, Fan C, Zhang X, He X, Pavlick A, Gutierrez MC, Renshaw L, Larionov AA, Faratian D, Hilsenbeck SG, Perou CM, Lewis MT, Rosen JM, and Chang JC. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl. Acad. Sci, USA, 2009;106(33):13820-5. Epub 2009 Aug 3.PMID: 19666588

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

Wright MH, Hollingshead MG, Herschkowitz JI, Robles AI, Anver MR, Perou CM, and Varticovski

L. Molecular analysis reveals heterogeneity of mouse mammary tumors conditionally mutant for Brca1. Molecular Cancer 2008, 7:29. PMID: 18394172

Li Z, Tognon CE, Godinho FJ, Yasaitis L, Hock H, Herschkowitz JI, Lannon CL, Cho E, Kim S, Bronson RT, Perou CM, Sorensen PH, and Orkin SH. ETV6-NTRK3 fusion oncogene initiates breast cancer from committed mammary progenitors via activation of AP1 complex. Cancer Cell. 2007 Dec;12(6):542-58. PMID: 18068631

Bultman SJ, Herschkowitz JI, Godfrey V, Gebuhr TC, Yaniv M, Perou CM, and Magnuson T. Characterization of mammary tumors from Brg1 heterozygous mice Oncogene 2007 Jul 16; [Epub ahead of print] PMID: 17637742

Burkart MF, Wren JD, Herschkowitz JI, Perou CM, and Garner HR. Clustering microarray-derived gene lists through implicit literature connections. Bioinformatics 2007 May 30; [Epub ahead of print] PMID: 17537751

Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, and Perou CM. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biology 2007 May 10;8(5):R76. PMID: 17493263

Troester MA, Herschkowitz JI, Oh DS, He X, Hoadley KA, Barbier CS, Perou CM. Gene expression patterns associated with p53 status in breast cancer. BMC Cancer. 2006 Dec 6;6:276. PMID: 17150101

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