DF/HCC Program Affiliation

Breast Cancer
Gynecologic Cancers

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The Drapkin Lab

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

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