Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 15, Pages -Publisher
MDPI
DOI: 10.3390/ijms23158086
Keywords
miR-489; breast cancer; estrogen receptor; tamoxifen resistance; CRISPR; Cas9
Funding
- NIH [R01CA178386, R21CA252360]
- USC ASPIRE-1 grant [R01CA218578]
- NSF [1853365]
- American Cancer Society Research Scholar Grant [RSG-19-194-01-CSM]
- USC SPARC graduate fellowship
- Direct For Mathematical & Physical Scien
- Division Of Mathematical Sciences [1853365] Funding Source: National Science Foundation
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The study reveals the crucial role of miR-489 in regulating estrogen signaling and tamoxifen resistance in breast cancer. miR-489 negatively regulates estrogen receptor signaling and overexpression of miR-489 can restore tamoxifen sensitivity in resistant cells. Additionally, miR-489 disrupts the positive feed-forward loop in breast cancer cells and functions as a transcription factor.
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 alpha (ER alpha) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Er alpha 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.
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