POR overexpression induces tamoxifen‐resistance in breast cancer through the STAT1/c‐Myc pathway

Abstract

Breast cancer is the most common cancer in women worldwide. Although tamoxifen (TAM), a selective estrogen receptor (ER) modulator, is widely used to treat ER‐positive breast cancers, resistance to TAM remains a major clinical problem. NADPH‐dependent cytochrome P450 reductase (POR) is known to participate in drug metabolism and steroid metabolism. Recent studies showed that high POR expression was correlated with poor outcomes in triple‐negative breast cancer (TNBC), and POR might be a prognostic biomarker in TNBC. However, the role of POR in TAM resistance is still elusive. In this study, we found that high POR expression was associated with poor prognosis of ER‐positive and TAM‐treated breast cancer patients. In addition, COX analysis showed that POR expression was an independent prognostic biomarker for ER‐positive as well as TAM‐treated breast cancer patients. Furthermore, our results suggested that POR overexpression promoted TAM resistance by activating the STAT1/c‐Myc pathway in ER‐positive breast cancer cells. Immunohistochemical analysis showed that high POR/STAT1 expression was correlated with poor prognosis in TAM‐treated breast cancer patients. Notably, combined treatment with TAM and a specific STAT1 inhibitor Fludarabine was more effective for inhibiting TAM‐resistant breast cancer cells. Altogether, our findings suggested that POR overexpression induced TAM resistance through STAT1/c‐Myc pathway and might serve as an independent prognostic biomarker in TAM‐treated breast cancer patients. Combining TAM and STAT1 inhibitors might be an effective strategy for treating POR‐induced TAM‐resistant breast cancer.

Identification of circRNA-miRNA-mRNA network in luminal breast cancers by integrated analysis of microarray datasets

“…A previous study has identified that suggest that increased STAT1 signaling is important in endocrine resistance and that STAT inhibitors may represent potential therapies in endocrine-resistant breast cancer (Huang et al, 2014;Chen et al, 2023). STAT1/c-Myc pathway is involved in PORinduced TAM-resistant breast cancer (Chen et al, 2023). The present study reveals a possible tamoxifen-resistant mechanism by which hsa_circ_0086735 may sponge miR-1296-5p, indirectly moderating STAT1 and contributing to tamoxifen resistance.…”

“…Depletion of STAT1 can decrease levels of ERα protein and cell proliferation in tamoxifen-resistant cell line LCC2 (Hou et al, 2018). A previous study has identified that suggest that increased STAT1 signaling is important in endocrine resistance and that STAT inhibitors may represent potential therapies in endocrine-resistant breast cancer (Huang et al, 2014;Chen et al, 2023). STAT1/c-Myc pathway is involved in PORinduced TAM-resistant breast cancer (Chen et al, 2023).…”