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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 Article has an altmetric score of 2

MEL-18 loss mediates estrogen receptor–α downregulation and hormone independence

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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 4

The loss of MEL-18 induces resistance to antiestrogen therapy.

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The loss of MEL-18 induces resistance to antiestrogen therapy.
(A) Cell ...
(A) Cell viabilities following treatment with the indicated doses (μM) of tamoxifen (Tam) or ethanol (vehicle) for 5 days were analyzed via the MTT assay. The data are presented as mean ± SD (n = 3). (B) NOD/SCID mice injected with control or MEL-18–silenced cells following implantation with or without E2 pellets were administered Tam for 4 weeks (n = 8 per group; mean ± SEM). P values for multiple comparisons (4 groups: shCon/E2, shMEL/E2, shCon/E2+Tam, and shMEL/E2+Tam) were calculated via Welch ANOVA followed by Dunnett’s T3 test. **P = 0.004 vs. shCon/E2+Tam; †P = 0.019 vs. shCon/E2; P = NS vs. shMEL/E2; ‡P < 0.001 (shCon/E2+Tam vs. shMEL/E2+Tam) and P = 0.043 (shCon/E2 vs. shMEL/E2) based on RM ANOVA. (C) IHC for ER-α and PR in the xenografted tumors from the indicated groups of mice (mean ± SEM of 3 mice). *P < 0.05 vs. shCon (2-tailed Student’s t test). Scale bars: 100 μm. (D) Tumor growth curves for NOD/SCID mice implanted with control or MEL-18–overexpressing MDA-MB-468 cells treated with Tam (5 mg/ pellet) or placebo (n = 8 per group; mean ± SEM). P < 0.001 (days), P = 0.026 (group × days) based on RM ANOVA. **P = 0.006 vs. Con/Tam; †P = 0.026 vs. MEL-18/placebo (post hoc LSD test). (E) Analysis of OS and DFS according to MEL-18 expression in 103 Tam-treated ER-α–positive human breast tumors using the Kaplan-Meier method.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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