title: BRCA1-IRIS inactivation sensitizes ovarian tumors to cisplatin.
abstract: Ovarian cancer is the first in mortalities among gynecologic cancers in the United States, often due to late diagnosis and/or acquired platinum-resistant recurrences. This study investigates whether BRCA1-IRIS is a novel treatment target for ovarian cancers and in platinum-resistant recurrences. Here we show that more than half of the ovarian cancer samples analyzed showed BRCA1-IRIS and survivin overexpression and lacked nuclear FOXO3a expression. Normal ovarian epithelial cells overexpressing BRCA1-IRIS formed metastasis in mice when injected in the peritoneal cavity, whereas aggressive ovarian cancer cell lines failed to form tumors or metastases in mice when BRCA1-IRIS was silenced in them. We show that BRCA1-IRIS activates two autocrine signaling loops, brain-derived neurotrophic factor/tyrosine kinase B receptor (BDNF/TrkB) and neuregulin 1 (NRG1)/ErbB2. These loops are involved in anoikis resistance and metastasis promotion. These loops operate in several ovarian cancer cell lines, and BRCA1-IRIS silencing or inactivation using a novel inhibitory peptide renders both non-functional and promoted cell death. In a mouse xenograft model, BRCA1-IRIS inactivation using this novel inhibitory peptide resulted in significant reduction in ovarian tumor growth. More importantly, this treatment sensitized ovarian tumors to low cisplatin concentrations. Taken together, these data strongly suggest that BRCA1-IRIS and/or BDNF/TrkB and NRG1/ErbB2 could serve as rational therapeutic targets for advanced ovarian cancers.
authors.affiliation: Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Paul
authors.affiliation: Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Blanchard
authors.affiliation: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ridgway
authors.affiliation: Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: ElShamy
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002945:Cisplatin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D010455:Peptides; D000077022:Survivin; D002945:Cisplatin