title: MEL-18 loss mediates estrogen receptor-α downregulation and hormone independence.
abstract: The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor-α (ER-α, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-α-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-α and the progesterone receptor (PR), MEL-18 overexpression restored ER-α expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI-1/RING1B-mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer.
authors.forename: Jeong-Yeon
authors.initials: JY
authors.lastname: Lee
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Won
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Park
authors.forename: Hye-Yeon
authors.initials: HY
authors.lastname: Kim
authors.forename: Hee-Joo
authors.initials: HJ
authors.lastname: Choi
authors.forename: Dong-Hui
authors.initials: DH
authors.lastname: Shin
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.forename: Jong-Kyu
authors.initials: JK
authors.lastname: Woo
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Oh
authors.forename: Taekwon
authors.initials: T
authors.lastname: Son
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Choi
authors.forename: Sehwan
authors.initials: S
authors.lastname: Kim
authors.forename: Hyung-Yong
authors.initials: HY
authors.lastname: Kim
authors.forename: Kijong
authors.initials: K
authors.lastname: Yi
authors.forename: Ki-Seok
authors.initials: KS
authors.lastname: Jang
authors.forename: Young-Ha
authors.initials: YH
authors.lastname: Oh
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D003546:Cysteine Endopeptidases; D019008:Drug Resistance, Neoplasm; D010450:Endopeptidases / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D004967:Estrogens; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D063150:Polycomb Repressive Complex 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011374:Progesterone; D016016:Proportional Hazards Models; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism; D058207:Sumoylation / Q000187:drug effects; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D047628:Estrogen Receptor alpha; D004967:Estrogens; D009025:Morpholines; D009363:Neoplasm Proteins; D063150:Polycomb Repressive Complex 1; D011374:Progesterone; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D016329:Sp1 Transcription Factor; D013629:Tamoxifen; D016159:Tumor Suppressor Protein p53; C506487:ESR1 protein, human; C571178:NVP-BKM120; C489348:PCGF2 protein, human; C108209:SP1 protein, human; C495901:TP53 protein, human; C508053:ERBB2 protein, human; C404512:SENP1 protein, human
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