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

J Clin Invest. 2015 May;125(5):1801-14. doi: 10.1172/JCI73743. Epub 2015 Mar 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / administration & dosage
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / biosynthesis
  • Biomarkers, Tumor / genetics
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / drug therapy
  • Carcinoma, Ductal, Breast / metabolism*
  • Carcinoma, Ductal, Breast / mortality
  • Carcinoma, Ductal, Breast / pathology
  • Cysteine Endopeptidases
  • Drug Resistance, Neoplasm
  • Endopeptidases / metabolism
  • Estrogen Receptor alpha / analysis
  • Estrogen Receptor alpha / biosynthesis*
  • Estrogen Receptor alpha / genetics
  • Estrogens*
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Morpholines / administration & dosage
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Neoplasm Transplantation
  • Neoplasms, Hormone-Dependent / drug therapy
  • Neoplasms, Hormone-Dependent / metabolism*
  • Neoplasms, Hormone-Dependent / mortality
  • Neoplasms, Hormone-Dependent / pathology
  • Polycomb Repressive Complex 1 / deficiency
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb Repressive Complex 1 / physiology*
  • Progesterone*
  • Proportional Hazards Models
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Processing, Post-Translational / drug effects
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • Receptor, ErbB-2 / analysis
  • Receptors, Progesterone / analysis
  • Receptors, Progesterone / biosynthesis*
  • Receptors, Progesterone / genetics
  • Sp1 Transcription Factor / metabolism
  • Sumoylation / drug effects
  • Tamoxifen / administration & dosage
  • Tamoxifen / pharmacology
  • Tamoxifen / therapeutic use
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / mortality
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Aminopyridines
  • Antineoplastic Agents, Hormonal
  • Biomarkers, Tumor
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Estrogens
  • Morpholines
  • NVP-BKM120
  • Neoplasm Proteins
  • PCGF2 protein, human
  • RNA, Messenger
  • RNA, Neoplasm
  • Receptors, Progesterone
  • Sp1 Transcription Factor
  • SP1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Tamoxifen
  • Progesterone
  • Polycomb Repressive Complex 1
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Endopeptidases
  • SENP1 protein, human
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex