title: Müllerian inhibiting substance type II receptor (MISIIR): a novel, tissue-specific target expressed by gynecologic cancers.
abstract: OBJECTIVE
  Müllerian inhibiting substance type II receptor (MISIIR) is expressed by ovarian, breast, and prostate cancers [Masiakos PT, et al. Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) Type II Receptor, bind, and are responsive to MIS. Clin Cancer Res 1999;5:3488-99; Hoshiya Y, et al. Mullerian inhibiting substance promotes interferon {gamma}-induced gene expression and apoptosis in breast cancer cells. J Biol Chem 2003;278:51703-12; Hoshiya Y, et al. Mullerian inhibiting substance induces NFkB signaling in breast and prostate cancer cells. Mol. Cell. Endocrinol. 2003;211:43-9. [1-3]]. We investigated the expression patterns of MISIIR in benign and malignant gynecologic tissues and benign non-gynecologic tissues to better assess the relevance of MISIIR as a target for new therapeutic and diagnostic approaches to gynecologic cancers. Secondarily, we examined the impact of MISIIR expression on overall survival (OS) and disease-free survival (DFS) in a cohort of epithelial ovarian cancers (EOC).
  
  
  METHODS
  Reverse-transcription polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemistry (IHC) were used to determine MISIIR expression. EOC cell lines (10), primary EOCs (12), and tissue microarrays (TMAs) containing benign gynecologic (179) and non-gynecologic tissues (25), EOC (182), endometrial carcinomas (109), uterine sarcomas (98), and ovarian dysgerminomas (22) were examined for MISIIR expression. Clinical data were collected for a cohort of 182 EOCs.
  
  
  RESULTS
  Ninety-two percent of primary EOCs and 44% of EOC cell lines expressed MISIIR mRNA. We observed moderate or strong MISIIR expression via IHC in the majority of gynecologic cancers: EOC 69% (125/182), ovarian dysgerminomas 77% (17/22), endometrial cancers 75% (82/109), uterine malignant mixed Müllerian tumors (MMMT) 59% (30/51), uterine leiomyosarcomas (LMS) 52% (15/29), and endometrial stromal sarcomas (ESS) 22% (4/18). Over 74% of normal non-gynecologic tissues did not express MISIIR. There was a significant correlation between MISIIR expression and improved OS (p=0.025, Chi square).
  
  
  CONCLUSIONS
  In the largest study to date, we report that MISIIR is highly expressed by a wide variety of gynecologic cancers, including cancers currently without effective systemic therapies. Low levels of expression in select non-gynecologic tissues coupled with high expression in gynecologic malignancies make MISIIR an attractive target for novel therapeutics and tumor-directed imaging in the management of gynecologic cancers. Further investigation into the impact of MISIIR expression and OS is also warranted.
authors.affiliation: Department of Gynecologic Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Bakkum-Gamez
authors.forename: Giovanni
authors.initials: G
authors.lastname: Aletti
authors.forename: Kriste A
authors.initials: KA
authors.lastname: Lewis
authors.forename: Gary L
authors.initials: GL
authors.lastname: Keeney
authors.forename: Bijoy M
authors.initials: BM
authors.lastname: Thomas
authors.forename: Isabelle
authors.initials: I
authors.lastname: Navarro-Teulon
authors.forename: William A
authors.initials: WA
authors.lastname: Cliby
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005833:Genital Neoplasms, Female / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018000:Receptors, Peptide / Q000096:biosynthesis* / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014162:Transfection
chemical_list: D012333:RNA, Messenger; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor