title: Patterns of Müllerian Inhibiting Substance Type II and Candidate Type I Receptors in Epithelial Ovarian Cancer.
abstract: The MIS pathway is a potential therapeutic target in epithelial ovarian cancer (EOC): signaling requires both type II (T2R) and type I receptors (T1R), and results in growth inhibition. MISR2 is expressed in EOC, but the prevalence and relative contributions of candidate T1R remain unknown. We sought to: a) determine expression of T1R in EOC; b) assess impact of T1R expression with clinical outcomes; c) verify MIS-dependent Smad signaling and growth inhibition in primary EOC cell cultures. Tissue microarrays (TMA) were developed for analysis of T1Rs (ALK2/3/6) and MISR2 expression. Primary cell cultures were initiated from ascites harvested at surgery which were used to characterize response to MIS. TMA's from 311 primary cancers demonstrated the most common receptor combinations were: MISR2+/ALK2+3+6+ (36%); MISR2+/ALK2+3+6- (34%); MISR2-/ALK2+3+6- (18%); and MISR2-/ALK2+3+6+ (6.8%). No differences in overall survival (OS) were noted between combinations. The ALK6 receptor was least often expressed T1R and was associated with lower OS in early stage disease only (p =0.03). Most primary cell cultures expressed MISR2 (14/22 (63.6%)): 95% of these express ALK 2 and ALK3, whereas 54.5% expressed ALK6. MIS-dependent Smad phosphorylation was seen in the majority of cultures (75%). Treatment with MIS led to reduced cell viability at an average of 71% (range: 57-87%) in primary cultures. MIS signaling is dependent upon the presence of both MISR2 and specific T1R. In the majority of EOC, the T1R required for MIS-dependent signaling are present and such cells demonstrate appropriate response to MIS.
authors.forename: E
authors.initials: E
authors.lastname: Basal
authors.forename: T
authors.initials: T
authors.lastname: Ayeni
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.forename: C
authors.initials: C
authors.lastname: Langstraat
authors.forename: P K
authors.initials: PK
authors.lastname: Donahoe
authors.forename: D
authors.initials: D
authors.lastname: Pepin
authors.forename: X
authors.initials: X
authors.lastname: Yin
authors.forename: E
authors.initials: E
authors.lastname: Leof
authors.affiliation: Department of Obstetrics and Gynecology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. cliby.william@mayo.edu.
authors.forename: W
authors.initials: W
authors.lastname: Cliby
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D054304:Anti-Mullerian Hormone / Q000494:pharmacology*; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
chemical_list: D020033:Protein Isoforms; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; C084621:anti-Mullerian hormone receptor; D054304:Anti-Mullerian Hormone; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I