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 2

MEL-18 positively regulates ESR1 and PR expression.

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MEL-18 positively regulates ESR1 and PR expression. (A) Heatmap generate...
(A) Heatmap generated from the microarray analysis of MCF-7 cells expressing either control (shCon) or MEL-18 shRNA (shMEL) showing the differential expression of the luminal and basal markers between the two groups. The Venn diagram shows the number of common genes between the MEL-18 target genes and the PAM305 gene list. (B) The MEL-18 target genes obtained from the microarray analysis were categorized according to gene function via GO enrichment analysis. (C) The MEL-18–silenced (shMEL) or MEL-18–overexpressing (MEL-18) breast cancer cells and control cells (shCon and Con) were cultured in DMEM containing 10% FBS for 48 hours, and the cell lysates were subjected to immunoblotting using the indicated antibodies. To detect ER-α protein expression in TNBC cells, more than 100 μg of lysate was used for immunoblotting. The relative immunoblot band densities are indicated at the bottom of each blot. n.d., not detected. A black line within the blot indicates that the bands were spliced from the equal lane in the same gel because of the expression of isoforms of PR at different molecular weights (lower, PR-A, 81 kDa; upper, PR-B, 116 kDa). The data are representative of three independent experiments. (D and E) The mRNA levels of ER-α (ESR1) in the indicated stable cell lines were validated via qRT-PCR. The data represent the mean ± SD of triplicate measurements. *P < 0.05 vs. the controls (shCon or Con) based on 2-tailed Student’s t test.