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
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / administration & dosage
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Animals
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Antineoplastic Agents, Hormonal / pharmacology
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Antineoplastic Agents, Hormonal / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Biomarkers, Tumor / biosynthesis
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Biomarkers, Tumor / genetics
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism*
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Breast Neoplasms / mortality
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Breast Neoplasms / pathology
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Carcinoma, Ductal, Breast / drug therapy
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Carcinoma, Ductal, Breast / metabolism*
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Carcinoma, Ductal, Breast / mortality
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Carcinoma, Ductal, Breast / pathology
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Cysteine Endopeptidases
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Drug Resistance, Neoplasm
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Endopeptidases / metabolism
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Estrogen Receptor alpha / analysis
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Estrogen Receptor alpha / biosynthesis*
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Estrogen Receptor alpha / genetics
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Estrogens*
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Female
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Humans
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Kaplan-Meier Estimate
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Mice
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Morpholines / administration & dosage
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplasm Transplantation
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Neoplasms, Hormone-Dependent / drug therapy
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Neoplasms, Hormone-Dependent / metabolism*
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Neoplasms, Hormone-Dependent / mortality
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Neoplasms, Hormone-Dependent / pathology
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Polycomb Repressive Complex 1 / deficiency
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Polycomb Repressive Complex 1 / genetics
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Polycomb Repressive Complex 1 / physiology*
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Progesterone*
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Proportional Hazards Models
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Proteasome Endopeptidase Complex / metabolism
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Protein Processing, Post-Translational / drug effects
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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Receptor, ErbB-2 / analysis
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Receptors, Progesterone / analysis
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Receptors, Progesterone / biosynthesis*
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Receptors, Progesterone / genetics
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Sp1 Transcription Factor / metabolism
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Sumoylation / drug effects
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Tamoxifen / administration & dosage
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Tamoxifen / pharmacology
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Tamoxifen / therapeutic use
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Triple Negative Breast Neoplasms / drug therapy
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Triple Negative Breast Neoplasms / metabolism
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Triple Negative Breast Neoplasms / mortality
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Triple Negative Breast Neoplasms / pathology
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Tumor Suppressor Protein p53 / metabolism
Substances
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Aminopyridines
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Antineoplastic Agents, Hormonal
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Biomarkers, Tumor
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ESR1 protein, human
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Estrogen Receptor alpha
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Estrogens
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Morpholines
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NVP-BKM120
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Neoplasm Proteins
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PCGF2 protein, human
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RNA, Messenger
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RNA, Neoplasm
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Receptors, Progesterone
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Sp1 Transcription Factor
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SP1 protein, human
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TP53 protein, human
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Tumor Suppressor Protein p53
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Tamoxifen
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Progesterone
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Polycomb Repressive Complex 1
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ERBB2 protein, human
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Receptor, ErbB-2
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Endopeptidases
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SENP1 protein, human
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex