MEL-18 loss mediates estrogen receptor-alpha downregulation and hormone independence

Title
MEL-18 loss mediates estrogen receptor-alpha downregulation and hormone independence
Authors
장기석
Keywords
BREAST-CANCER CELLS; E3 UBIQUITIN LIGASE; TUMOR-SUPPRESSOR; EXPRESSION; SUMOYLATION; P53; RESISTANCE; ER; CHEMOTHERAPY; PROGRESSION
Issue Date
2015-04
Publisher
AMER SOC CLINICAL INVESTIGATION INC
Citation
JOURNAL OF CLINICAL INVESTIGATION, v. 125, NO 5, Page. 1801-1814
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-alpha (ER-alpha, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-alpha-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-alpha and the progesterone receptor (PR), MEL-18 overexpression restored ER-alpha 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 SUM01/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.
URI
http://www.jci.org/articles/view/73743http://hdl.handle.net/20.500.11754/24138
ISSN
0021-9738; 1558-8238
DOI
http://dx.doi.org/10.1172/JCI73743
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COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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