Abstract P6-05-06: Estrogen induced miR-489 acts as a negative feedback to confine uncontrolled estrogen signaling and cell proliferation in breast cancer

Abstract

Abstract Estrogen induced miR-489 acts as a negative feedback to confine uncontrolled estrogen signaling and cell proliferation in breast cancer. Mithil Soni1,2, Yogin Patel1,2,3, Ryann Shealy1, Hexin Chen1,2,4. 1Dept. of Biological Sciences, University of South Carolina, 2Center for colon cancer research, 3current location, National cancer institute, surgery branch, 4corrosponding author. Approximately 75% of diagnosed breast cancer tumors are Estrogen receptor positive tumors and are associated with better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Identification of novel molecular targets is necessary to combat such resistant tumors. In the current study, using microarray, qRT-PCR, western blot, luciferase reporter assay and immunofluorescence, we found that miR-489 is an estrogen regulated miRNA that negatively regulates estrogen signaling. Depletion of miR-489 using Anti-miR-489 siRNA or CRISPR-Cas9 significantly increased estrogen induced proliferation, colony formation ability and stem like cell population. Loss of miR-489 also induced estrogen independent proliferation. Mechanistically we found that depletion of miR-489 enhanced nuclear localization of estrogen receptor while restoration of miR-489 increased cytosolic ER and inhibited estrogen induced transcription. Furthermore, we found that miR-489 depletion also increases estrogen independent growth through activation of MAPK and PI3K-AKT pathway. We also observed loss of miR-489 in tamoxifen resistance breast cancer cell line and found increased resistance to tamoxifen upon miR-489 inhibition while miR-489 restoration sensitized Tamoxifen resistant cell lines. Clinical analysis of estrogen receptor positive breast cancer patient showed that ER+ve breast cancers with low miR-489 expression represents aggressive cancers with significant reduction in survival time. In summary, these results indicate potential role of miR-489 as a biomarker to predict aggressiveness of ER+ve breast cancer and response to tamoxifen therapy and can potentially be used as a therapeutic agent to treat or sensitize tamoxifen resistant tumors. Citation Format: Soni M, Patel Y, Shealy R, Chen H. Estrogen induced miR-489 acts as a negative feedback to confine uncontrolled estrogen signaling and cell proliferation in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-05-06.