NUPR1 contributes to endocrine therapy resistance by modulating BIRC5 expression and inducing luminal B-ERBB2 subtype-like characteristics in estrogen receptor-positive breast cancer cells.

Acquired resistance to endocrine therapy is a major clinical challenge in the treatment of luminal A [estrogen receptor (ER) and/or progesterone receptor (PR), human epidermal growth factor receptor 2 (ERBB2/HER2), and low Ki-67] breast cancer. Recently, molecular subtype conversion has been suggested as one of the possible causes of the development of drug-resistant breast cancer. However, the molecular mechanism underlying the molecular subtype conversion and the induction of endocrine therapy resistance in luminal A breast cancer is still incompletely understood. Here, we found that the ER MCF7-derived endocrine therapy-resistant MCF7-TamC3 breast cancer cells exhibit increased expression of an intrinsically disordered chromatin protein, NUPR1, compared to the parental luminal-A subtype like MCF7 breast cancer cells. Intriguingly, MCF7-TamC3 cells also exhibit characteristics that resemble the luminal B-ERBB2 breast tumor subtype, like the increased expression of ERBB2 and the increased sensitivity to monoclonal ERBB2-targeting antibody Trastuzumab . Kaplan-Meier analysis of expression cohorts of breast tumors showed that high mRNA expression levels correlate with poor overall and relapse-free survival in both endocrine therapy-treated ER and ERBB2-enriched breast cancer patients. Results of the bioinformatics analysis showed that the mRNA expression level is also correlated with the clinical grading of the Tamoxifen-treated ER primary breast cancer. The qPCR and the western blot analysis results revealed that NUPR1 positively regulates the expression of the epigenetic regulator HDAC5, the anti-apoptotic molecule BIRC5, and the mitogenic receptor ERBB2 in MCF7-TamC3 and the ERBB2-enriched subtype like SK-BR-3 breast cancer cells. Downregulation of NUPR1 increased the sensitivity to estrogen deprivation in MCF7-TamC3 cells and decreased the viability of SK-BR-3 cells . These findings indicate that dysregulation of NUPR1 promotes the development of estrogen independence in ER breast cancer cells in part through expression regulation of HDAC5, ERBB2, and BIRC5. Targeting NUPR1 or its downstream regulating molecules may offer a potential strategy for overcoming resistance to endocrine therapy in patients with ER breast cancer.