MEL-18 loss mediates estrogen receptor-alpha downregulation and hormone independence
- Authors
- Lee, Jeong-Yeon; Won, Hee-Young; Park, Ji-Hye; Kim, Hye-Yeon; Choi, Hee-Joo; Shin, Dong-Hui; Mang, Ju-Hee; Woo, Jong-Kyu; Oh, Seung-Hyun; Son, Taelmon; Choi, Jin-Woo; Kim, Sehwan; Kim, Hyung-Yong; Yi, Kijong; Jang, Ki-Seok; Oh, Young-Ha; Kong, Gu
- Issue Date
- May-2015
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Citation
- JOURNAL OF CLINICAL INVESTIGATION, v.125, no.5, pp.1801 - 1814
- Journal Title
- JOURNAL OF CLINICAL INVESTIGATION
- Volume
- 125
- Number
- 5
- Start Page
- 1801
- End Page
- 1814
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/10583
- DOI
- 10.1172/JCI73743
- ISSN
- 0021-9738
- 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.
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