TY - JOUR
T1 - Müllerian inhibiting substance type II receptor (MISIIR)
T2 - A novel, tissue-specific target expressed by gynecologic cancers
AU - Bakkum-Gamez, Jamie N.
AU - Aletti, Giovanni
AU - Lewis, Kriste A.
AU - Keeney, Gary L.
AU - Thomas, Bijoy M.
AU - Navarro-Teulon, Isabelle
AU - Cliby, William A.
N1 - Funding Information:
Supported by a grant from the Minnesota Ovarian Cancer Alliance (MOCA) to WAC.
Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2008/1
Y1 - 2008/1
N2 - 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.
AB - 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.
KW - Endometrial cancer
KW - Epithelial ovarian cancer
KW - Müllerian inhibiting substance (MIS)
KW - Müllerian inhibiting substance type II receptor (MISIIR)
KW - Ovarian dysgerminoma
KW - Uterine sarcoma
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UR - http://www.scopus.com/inward/citedby.url?scp=37449021993&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2007.09.010
DO - 10.1016/j.ygyno.2007.09.010
M3 - Article
C2 - 17988723
AN - SCOPUS:37449021993
SN - 0090-8258
VL - 108
SP - 141
EP - 148
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 1
ER -