Endometrial cancer is a receptor-mediated target for Mullerian Inhibiting Substance

Abstract

Mullerian Inhibiting Substance (MIS), a 140-kDa homodimer glycoprotein member of the TGF-β superfamily of biological-response modifiers, causes regression of the Mullerian ducts in developing male embryos. MIS also can induce growth arrest and apoptosis in ovarian and cervical cancer cell lines. The embryonic progenitor of the ovarian and cervical epithelium is the coelomic epithelium, the same tissue that regresses under the direction of MIS in the male. The endometrium and uterus also arise from the coelomic epithelium and the Mullerian ducts. Here, we show that both normal human endometrium and endometrial cancers express the receptor for MIS and that MIS can inhibit the proliferation of a number of human endometrial cancer cell lines that express the MIS type II receptor. In the representative endometrial cancer cell line AN3CA, MIS affects the expression of key cell-cycle regulatory proteins. This work broadens the scope of tumors that MIS can potentially control and, by elucidating the MIS signaling pathway, identifies other potential avenues for intervention

Increased expression of antimüllerian hormone and its receptor in endometriosis

“…In particular, activin A (24,25), bone morphogenetic proteins (BMPs), and growth differentiation factors (26) modulate cell differentiation and proliferation, apoptosis, and tissue remodeling, and AMH in endometrial cell cultures increases apoptosis (16). The effect of AMH on proliferation and cell death was even more pronounced in cultured endometrial/cervical cancer cells (18,27), as well as in endometrium of patients with endometriosis (16,17). The lack of significant changes in AMH/AMHRII mRNA levels throughout the menstrual cycle reported in the present study, suggests a sex hormoneindependent expression like that of BMP-4, another TGF-b family member whose expression is dysregulated in endometrium of women with endometriosis (28).…”

“…An effect of AMH on cell proliferation and cell death has been found also in endometrial/cervical cancer cells (17,18), and even more pronounced in cultures of endometrial cells from endometriotic patients, where AMH was found to induce significant increase of annexin V (17).…”

Identification of large-scale characteristic genes of Müllerian inhibiting substance in human ovarian cancer cells

“…Although similar cell cycle regulation by MIS has been investigated in other cancers (20,36), the systemic molecular circuit of this cell cycle regulation in ovarian cancer still remains unknown. Furthermore, as several lines of evidence suggest that MIS is a multi-functional hormone, the comprehensive molecular signature which is mediated by MIS in cells needs to be elucidated.…”

Mullerian Inhibiting Substance enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancer

“…For example, MIS exerts its effect in the embryonic urogenital ridge by activating MISRII, Alk2 and Alk3, and the Smad 1͞5͞8 differentiation and growth inhibitory pathway (35). In addition, MIS up-regulates pocket proteins p130 and p107 in human ovarian (10) and endometrial cancer cell lines (9). These proteins inhibit proliferation and͞or up-regulate cell cycle inhibitors in human ovarian and cervical carcinoma cell lines to cause cell cycle arrest.…”

“…It is anticipated that exogenous recombinant human MIS (rhMIS) will be nontoxic as a single agent and that it can be used effectively in combination with chemotherapy drugs to lower their toxicity. We originally hypothesized that cancers of Mullerian origin that expressed MISRII could be targets for MIS treatment (4)(5)(6)(7)(8)(9), focusing first on ovarian cancers because they are derived from an MISsensitive surface or coelomic epithelium (10) and have the worst prognosis of all female reproductive tumors. Furthermore, ovarian ascites cells are also accessible ex vivo to examine biomarkers that may predict their response and mechanisms of biologic effect.…”