DF/HCC Program Affiliation

Gynecologic Cancer
Breast Cancer

Lab Website

HMS BBS Program

Research Abstract

Research in the Drapkin laboratory focuses on understanding the pathogenesis and genetic alterations involved in women’s cancers with a specific interest in ovarian cancer. A major goal is to translate these important biological principles into clinically useful diagnostic and therapeutic tools. To accomplish these goals, the laboratory integrates genomic studies of human ovarian cancer, new culture model systems, and rigorous protein biochemistry and molecular biology to explore three complementary approaches:

Ovarian cancer genetics
Mutations in BRCA1 account for 5-10 percent of all ovarian and breast cancers. We recently identified and characterized a BRCA1-interacting protein called BRIP1. We showed that BRIP1 is a DNA helicase that functions together with BRCA1 to mediate efficient repair of DNA double strand breaks. Moreover, we found that in a small number of early-onset breast and ovarian cancers, in which the BRCA1 and BRCA2 genes are normal, the BRIP1 gene carries alterations that encode defective helicase proteins. These observations provide a biochemical link between disease development and BRIP1 activity. More recently, we reported the first example of loss of heterozygosity (LOH) for BRIP1 in a breast carcinoma from a woman with early onset disease. This finding further supports a tumor suppressor role for BRIP1. We are actively pursuing studies to define the biological function of BRIP1.

Pathogenesis
Ovarian cancer is heterogeneous disease thought to arise from the ovarian surface epithelium (OSE) but a clear understanding of the processes underlying neoplastic transformation of this epithelium is lacking. Recent studies show that the fallopian tubal fimbria, rather than the OSE, is a common site for early serous carcinomas, the most lethal form of the disease. In collaboration with the laboratory of Dr. Crum, we found that the tubal fimbria is the preferred site for the development of in situ carcinomas. In addition, we found normal-appearing precursor lesions, called ‘p53 signatures’ that harbor p53 mutations and evidence of DNA damage. We recently developed a novel ex-vivo culture model system that enables us to study the biological properties of the fallopian tube fimbria and define genotoxic stressors that predispose the serous cells to neoplastic transformation.

Biomarkers
Using genome-scale approaches, we are searching for biomarkers of ovarian cancer that, once characterized, can be developed into clinical tools for early detection. We identified human epididymis protein 4 (HE4) as a glycoprotein that is overexpressed and secreted by ovarian cancers. We further showed that HE4 circulates in the bloodstream of women with ovarian cancer. Our studies contributed to the 2008 approval by Food and Drug Administration of an HE4 serum test to monitor women with pelvic masses. Interestingly, the HE4 gene resides on chromosome 20q13, a region that is commonly amplified in ovarian cancers. Our analysis shows that a trio of proteins that are encoded on 20q13 is overexpressed in ovarian cancer, including HE4, Elafin, and SLPI. Work in progress indicates that one of these biomarkers, Elafin, confers a proliferative advantage to tumor cells and is under the control of the NF-kB pathway. We are currently working on defining the molecular mechanism of Elafin’s mitogenic properties.

Publications

• Levanon K, Crum C, Drapkin R.New insights into the pathogenesis of serous ovarian cancer and its clinical impact.J Clin Oncol 2008 Nov 10;26(32):5284-93.
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• Drapkin R, Clauss A, Skates S.Urokinase-type plasminogen activator receptor: a beacon of malignancy?.Clin Cancer Res 2008 Sep 15;14(18):5643-5.
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• De Nicolo A, Tancredi M, Lombardi G, Flemma CC, Barbuti S, Di Cristofano C, Sobhian B, Bevilacqua G, Drapkin R, Caligo MA.A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germ-line mutation impairs protein stability and function.Clin Cancer Res 2008 J
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• Scholler N, Lowe KA, Bergan LA, Kampani AV, Ng V, Forrest RM, Thorpe JD, Gross JA, Garvik BM, Drapkin R, Anderson GL, Urban N.Use of yeast-secreted in vivo biotinylated recombinant antibodies (Biobodies) in bead-based ELISA.Clin Cancer Res 2008 May 1;14(9
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• Garrett LA, Vargas SO, Drapkin R, Laufer MR.Does the fimbria have an embryologic origin distinct from that of the rest of the fallopian tube?.Fertil Steril 2008 Mar 17.
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• Crum CP, Drapkin R, Kindelberger D, Medeiros F, Miron A, Lee Y.Lessons from BRCA: The Tubal Fimbria Emerges as an Origin for Pelvic Serous Cancer.Clin Med Res 2007 Mar;5(1):35-44.
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• Silver DP, Dimitrov SD, Feunteun J, Gelman R, Drapkin R, Lu SD, Shestakova E, Velmurugan S, Denunzio N, Dragomir S, Mar J, Liu X, Rottenberg S, Jonkers J, Ganesan S, Livingston DM.Further evidence for BRCA1 communication with the inactive X chromosome.Cel
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• Erkko H, Xia B, Nikkila J, Schleutker J, Syrjakoski K, Mannermaa A, Kallioniemi A, Pylkas K, Karppinen SM, Rapakko K, Miron A, Sheng Q, Li G, Mattila H, Bell DW, Haber DA, Grip M, Reiman M, Jukkola-Vuorinen A, Mustonen A, Kere J, Aaltonen LA, Kosma VM, Ka
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• Crum CP, Drapkin R, Miron A, Ince TA, Muto M, Kindelberger DW, Lee Y.The distal fallopian tube: a new model for pelvic serous carcinogenesis.Curr Opin Obstet Gynecol 2007 Feb;19(1):3-9.
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• Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, Cramer DW, McKeon FD, Crum CP.A candidate precursor to serous carcinoma that originates in the distal fallopian tube.J Pathol 2007 Jan;211(1):26-35.
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• Drapkin R, von Horsten HH, Lin Y, Mok SC, Crum CP, Welch WR, Hecht JL.Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas.Cancer Res 2005 Mar 15;65(6):2162-9.
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• Drapkin R, Crum CP, Hecht JL.Expression of candidate tumor markers in ovarian carcinoma and benign ovary: evidence for a link between epithelial phenotype and neoplasia.Hum Pathol 2004 Aug;35(8):1014-21.
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• Cantor S, Drapkin R, Zhang F, Lin Y, Han J, Pamidi S, Livingston DM.The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations.Proc Natl Acad Sci U S A 2004 Feb 24;101(8):2357-62.
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• Fuchs M, Gerber J, Drapkin R, Sif S, Ikura T, Ogryzko V, Lane WS, Nakatani Y, Livingston DM.The p400 complex is an essential E1A transformation target.Cell 2001 Aug 10;106(3):297-307.
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• Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S, Wahrer DC, Sgroi DC, Lane WS, Haber DA, Livingston DM.BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function.Cell 2001 Apr 6;105(1):149-
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• Drapkin R, Le Roy G, Cho H, Akoulitchev S, Reinberg D.Human cyclin-dependent kinase-activating kinase exists in three distinct complexes.Proc Natl Acad Sci U S A 1996 Jun 25;93(13):6488-93.
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• Drapkin R, Reinberg D.Transcription. The essential twist.Nature 1994 Jun 16;369(6481):523-4.
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• Drapkin R, Reardon JT, Ansari A, Huang JC, Zawel L, Ahn K, Sancar A, Reinberg D.Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II.Nature 1994 Apr 21;368(6473):769-72.
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• Drapkin R, Sancar A, Reinberg D.Where transcription meets repair.Cell 1994 Apr 8;77(1):9-12.
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