AWARD NUMBER: W81XWH-11-2-0230 TITLE: Prevention of Ovarian High-Grade Serous Carcinoma by Elucidating Its Early Change

s 1. Sophia HL George, Anca Milea, Ramlogan Sowamber, Danielle Toccalino and Patricia Shaw. The role of estrogen receptor signaling in serous ovarian cancer. Cancer Research August 14, 2013 73:4765; doi:10.1158/1538-7445.AM2013-4765 2. Sophia HL George, Anca Milea, Ramlogan Sowamber, Danielle Toccalino and Patricia Shaw. STK11 and p53 synergy in fallopian tube epithelial and high-grade serous cancer (September 2013). Advances in Ovarian Cancer Research: From Concept to Clinic conference. Oral Presentations: Sophia HL George Origins of ovarian cancer, the biology of premalignancy, and cancer health disparities. AACR The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved on December 6 9, 2013 in Atlanta, GA. Patricia A Shaw LKB1 – Does it have a role in early ovarian cancer? 4th Annual Ovarian Cancer Symposium Prevention and Early Detection of Ovarian Cancer. May 2013, Memorial Sloan Kettering Cancer Center, New York, NY Patricia A Shaw Pathology of Ovarian Cancer. Breast and Ovarian Cancer in the Caribbean: Prevention, Diagnosis and Treatment. Women’s Cancer in the Caribbean Workshop, Dominica. May 2013, Roseau, Dominica George HL Early events in High Grade Serous Cancer Development. HL Women’s Cancer in the Caribbean Workshop, Dominica. May 2013, Roseau, Dominica Section III. Problem Areas for Project 3 We do not identify potential problems at this moment. These scientific results have important implications for the development of HGSC. The in vitro results using p53 and LKB1 inhibition identify a functional synergy between these two alterations leading to significant decrease in ciliated cells. These cells maintain fallopian tube epithelial markers such as pax8 and E-cadherin, identified in normal fallopian tube epithelium. These results indicate that our in vitro model closely mimics the normal/p53 signature in vivo conditions and that LKB1 inactivation represents a very early event in tumor formation. Section IV. Future Work in Project 3 Further immunohistochemical characterization of STICs will be performed because it is important in identifying candidate genes that may be utilized for metastatic cell transformation. For example, analysis of the Rb pathway in STICs has revealed non-synonymous alterations that go on to stratify tumors with clinical outcome differences. Furthermore, we will perform in depth analysis of primary fallopian tube cell lines with different molecular alterations, has revealed that although certain metastatic characteristics may be adopted, such as increased proliferation, anchorage independent growth and colonization of milky spots, these cells are not necessarily able to form tumors and colonize the mouse peritoneal cavity. REFERENCES: 1. Jazaeri AA, Bryant JL, Park H, et al. Molecular requirements for transformation of fallopian tube epithelial cells into serous carcinoma. Neoplasia 2011; 13(10):899-911 2. Karst AM, Levanon K, Drapkin R. Modeling high-grade serous ovarian carcinogenesis from the fallopian tube. Proc Natl Acad Sci U S A 2011; 108(18):7547-52. 3. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474(7353):609-15. 4. George SH, Greenaway J, Milea A, et al. Identification of abrogated pathways in fallopian tube epithelium from BRCA1 mutation carriers. J Pathol 2011; 225(1):106-17. 5. Wang J, Sarkar TR, Zhou M, et al. CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD)mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage. Proc Natl Acad Sci U S A 2010; 107(37):16131-6. APPENDICES: 1. Retinoblastoma Pathway Deregulatory Mechanisms Determine Clinical Outcome in High Grade Serous