Unknown

Dataset Information

0

MEL-18 loss mediates estrogen receptor-? 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-? (ER-?, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-?-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-? and the progesterone receptor (PR), MEL-18 overexpression restored ER-? 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.

SUBMITTER: Lee JY 

PROVIDER: S-EPMC4463188 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

altmetric image

Publications


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 o  ...[more]

Similar Datasets

| S-EPMC5325369 | biostudies-literature
| S-EPMC10997519 | biostudies-literature
| S-EPMC4718885 | biostudies-literature
2015-05-01 | GSE64716 | GEO
2012-11-14 | E-MTAB-1368 | biostudies-arrayexpress
2015-05-01 | E-GEOD-64716 | biostudies-arrayexpress
| PRJEB653 | ENA
| S-EPMC3840081 | biostudies-literature
2024-02-23 | GSE251644 | GEO
| S-EPMC8352984 | biostudies-literature