MEL-18 loss mediates estrogen receptor–α downregulation and hormone independence
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
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
View: Text | PDF
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

×

Figure 7

Proposed models for the regulation of hormone-dependent breast cancer by MEL-18.

Options: View larger image (or click on image) Download as PowerPoint
Proposed models for the regulation of hormone-dependent breast cancer by...
(A) Schematic model of the regulation of SUMO-dependent ER-α transcription by MEL-18. The loss of MEL-18 enhances SUMO activation via direct binding between the SUMO E2 enzyme UBC9 and its substrate. Moreover, MEL-18 depletion inhibits the deSUMOylation activity of SENP1 by enhancing the BMI-1/RING1B E3 ubiquitin ligase complex–mediated ubiquitin-proteasomal degradation of SENP1. Via these two pathways, MEL-18 inhibits the SUMOylation of p53; alternatively, MEL-18 modulates SP1 SUMOylation via the SENP1-mediated deSUMOylation pathway. Increasing p53 and SP1 SUMOylation via MEL-18 silencing inhibits their recruitment to the ER-α promoter and downregulates ER-α expression. (B) Proposed model for the regulation of the balance between hormone dependence and independence by the polycomb protein MEL-18 in human breast cancer. In luminal breast cancer, MEL-18 contributes to the maintenance of the expression of the hormone receptors ER-α and PR but not HER2 by inhibiting the SUMOylation of ER-α transcription factors and by enhancing ER-α–dependent transcriptional activity, respectively. However, when MEL-18 expression is lost during breast cancer progression, the tumor develops hormone independence and resistance to antihormonal therapy, phenotypes of hormone receptor–negative breast cancers, including TNBC, which is characterized by the loss of ER-α and PR expression and the lack of HER2 amplification. Therefore, MEL-18 acts as a modulator of hormone receptor expression and a critical determinant of hormone dependence and independence in human breast cancer. SU, SUMOylation; TFs, transcription factors.