buparlisib and Carcinoma--Ductal--Breast

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.

Topics: Aminopyridines; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Cysteine Endopeptidases; Drug Resistance, Neoplasm; Endopeptidases; Estrogen Receptor alpha; Estrogens; Female; Humans; Kaplan-Meier Estimate; Mice; Morpholines; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Polycomb Repressive Complex 1; Progesterone; Proportional Hazards Models; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Receptor, ErbB-2; Receptors, Progesterone; RNA, Messenger; RNA, Neoplasm; Sp1 Transcription Factor; Sumoylation; Tamoxifen; Triple Negative Breast Neoplasms; Tumor Suppressor Protein p53