MEL-18 loss mediates estrogen receptor–α downregulation and hormone independence
Jeong-Yeon Lee, … , Young-Ha Oh, Gu Kong
Jeong-Yeon Lee, … , Young-Ha Oh, Gu Kong
Published March 30, 2015
Citation Information: J Clin Invest. 2015;125(5):1801-1814. https://doi.org/10.1172/JCI73743.
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Research Article Oncology

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

Jeong-Yeon Lee, Hee-Young Won, Ji-Hye Park, Hye-Yeon Kim, Hee-Joo Choi, Dong-Hui Shin, Ju-Hee Kang, Jong-Kyu Woo, Seung-Hyun Oh, Taekwon Son, Jin-Woo Choi, Sehwan Kim, Hyung-Yong Kim, Kijong Yi, Ki-Seok Jang, Young-Ha Oh, Gu Kong

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Figure 3

MEL-18 depletion abrogates ER-α–dependent transcriptional activity and induces estrogen-independent tumor growth.

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MEL-18 depletion abrogates ER-α–dependent transcriptional activity and i...
(A–C) ERE luciferase assay (A) and qRT-PCR analysis of TFF1 (also known as pS2) and PR (PGR) expression levels (B and C) in the control and MEL-18–silenced or MEL-18–overexpressing cell lines in the presence or absence of E2 (10 nM in MCF-7 cells or 20 nM in MDA-MB-468 cells) for 24 hours. The error bars represent the mean ± SD of triplicate experiments. *P < 0.05 compared with the control (2-tailed Student’s t test). (D) The effect of MEL-18 knockdown on E2-independent breast tumor growth. Control or shMEL MCF-7 cells were transplanted into the mammary fat pads of NOD/SCID mice (n = 8) in the absence of E2 treatment. Tumor size was monitored to assess mouse xenograft tumor growth. *P < 0.05 (group × days) based on RM ANOVA from day 0 to the indicated days. P < 0.001 (days; RM ANOVA). (E) IHC for MEL-18, ER-α, and PR in the indicated samples from three independent xenografted mice. Scale bars: 100 μm. The data in D and E are presented as the mean ± SEM (n = 8 and n = 3, respectively, independent experiments). *P < 0.05 vs. shCon (2-tailed Student’s t test).