title: Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer.
abstract: Ovarian cancer cells express both estrogen receptor α (ERα) and ERβ, and hormonal therapy is an attractive treatment option because of its relatively few side effects. However, estrogen was previously shown to have opposite effects in tumors expressing ERα compared with ERβ, indicating that the two receptor subtypes may have opposing effects. This may explain the modest response to nonselective estrogen inhibition in clinical practice. In this study, we aimed to investigate the effect of selectively targeting each ER subtype on ovarian cancer growth. Ovarian cancer cell lines SKOV3 and OV2008, expressing both ER subtypes, were treated with highly selective ER modulators. Sodium 3'-(1-(phenylaminocarbonyl)-3,4-tetrazolium)-bis(4-methoxy-6-nitro) benzene sulfonic acid hydrate (XTT) assay revealed that treatment with 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP) (ERα antagonist) or 2,3-bis(4-hydroxy-phenyl)-propionitrile (DPN) (ERβ agonist) significantly suppressed cell growth in both cell lines. In contrast, 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) (ERα agonist) or 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]-pyrimidin-3-yl]phenol (PHTPP) (ERβ antagonist) significantly enhanced cell growth. These results were confirmed on a xenograft model where SKOV3 cells were injected s.c. into ovariectomized mice. We observed that the average size of xenografts in both the DPN-treated group and the MPP-treated group was significantly smaller than that for the vehicle-treated group. In addition, we found that phospho-AKT expressions in SKOV3 cells were reduced by 80% after treatment with MPP and DPN, indicating that the AKT pathway was involved. The combined treatment with MPP and DPN had a synergistic effect in suppressing ovarian cancer cell growth. Our findings indicate that targeting ER subtypes may enhance the response to hormonal treatment in women with ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, 6/F Professorial Block, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Karen Kar-Loen
authors.initials: KK
authors.lastname: Chan
authors.forename: Thomas Ho-Yin
authors.initials: TH
authors.lastname: Leung
authors.forename: David Wai
authors.initials: DW
authors.lastname: Chan
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.forename: Grace Tak-Yi
authors.initials: GT
authors.lastname: Lau
authors.forename: Stephanie Si
authors.initials: SS
authors.lastname: Liu
authors.forename: Michelle K-Y
authors.initials: MK
authors.lastname: Siu
authors.forename: Hextan Yuen-Sheung
authors.initials: HY
authors.lastname: Ngan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors*; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D020845:Selective Estrogen Receptor Modulators; D004958:Estradiol
keywords: SERMS; estrogen receptors; hormonal treatment; ovarian cancer