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MiR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer.

ABSTRACT: Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers.

SUBMITTER: Soni M

PROVIDER: S-EPMC9331933 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Breast cancer is the most common malignancy, and approximately 70% of breast cancers are estrogen receptor-α (ERα) positive. The anti-estrogen tamoxifen is a highly effective and commonly used treatment for patients with ER+ breast cancer. However, 30% of breast cancer patients fail adjuvant tamoxifen therapy and most of metastatic breast cancer patients develop tamoxifen resistance. Although increasing evidence suggests that microRNA (miRNA) dysregulation influences tamoxifen sensitivity, the mechanism of the cross-talk between miRNA and ERα signaling remains unclear. miR-575 has been reported to be involved in carcinogenesis and progression, however, the role of miR-575 in breast cancer remains limited. The aim of this study was to understand the mechanism of miR-575 in breast cancer tamoxifen resistance. Method: RT-qPCR was employed to assess miR-575 expression in breast cancer tissues and cell lines. The association of miR-575 expression with overall survival in patients with breast cancer was evaluated with KM plotter. Additionally, the effects of miR-575 on breast cancer proliferation and tamoxifen sensitivity were investigated both in vitro and in vivo. Bioinformatic analyses and luciferase reporter assays were performed to validate CDKN1B and BRCA1 as direct targets of miR-31-5p. The ERα binding sites in the miR-575 promoter region was validated with ChIP and luciferase assays. ERα interactions with CDKN1B, cyclin D1 or BRCA1 were determined by IP analysis, and protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Results: miR-575 levels were higher in ER+ breast cancer than in ER- breast cancer and patients with high miR-575 expression had a significantly poorer outcome than those with low miR-575 expression. ERα bound the miR-575 promoter to activate its transcription, and tamoxifen treatment downregulated miR-575 expression in ER+ breast cancer. Overexpression of miR-575 decreased tamoxifen sensitivity by targeting CDKN1B and BRCA1. CDKN1B and BRCA1 were both able to antagonize ERα activity by inhibiting ERα nuclear translocation and interaction with cyclin D1. Furthermore, miR-575 expression was found to be upregulated in ER+ breast cancer cell with acquired tamoxifen resistance, whereas depletion of miR-575 partially re-sensitized these cells to tamoxifen by regulation of CDKN1B. Conclusions: Our data reveal the ERα-miR-575-CDKN1B feedback loop in ER+ breast cancer, suggesting that miR-575 can be used as a prognostic biomarker in patients with ER+ breast cancer, as well as a predictor or a promising target for tamoxifen sensitivity.

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MiR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer.

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