Tamoxifen differentially regulates miR-29b-1 and miR-29a expression depending on endocrine-sensitivity in breast cancer cells

Abstract

Endocrine-resistance develops in ~ 40% of breast cancer patients after tamoxifen (TAM) therapy. Although microRNAs are dysregulated in breast cancer, their contribution to endocrine-resistance is not yet understood. Previous microarray analysis identified miR-29a and miR-29b-1 as repressed by TAM in MCF-7 endocrine-sensitive breast cancer cells but stimulated by TAM in LY2 endocrine-resistant breast cancer cells. Here we examined the mechanism for the differential regulation of these miRs by TAM in MCF-7 versus TAM-resistant LY2 and LCC9 breast cancer cells and the functional role of these microRNAs in these cells. Knockdown studies revealed that ERα is responsible for TAM regulation of miR-29b-1/a transcription. We also demonstrated that transient overexpression of miR-29b-1/a decreased MCF-7, LCC9, and LY2 proliferation and inhibited LY2 cell migration and colony formation but did not sensitize LCC9 or LY2 cells to TAM. Furthermore, TAM reduced DICER1 mRNA and protein in LY2 cells, a known target of miR-29. Supporting this observation, anti-miR-29b-1 or anti-miR-29a inhibited the suppression of DICER by 4-OHT. These results suggest miR-29b-1/a has tumor suppressor activity in TAM-resistant cells and does not appear to play a role in mediating TAM resistance.

Regulation of miR-29b-1/a transcription and identification of target mRNAs in CHO-K1 cells

“…These data agree with a report showing that miR-29b and miR-29a negatively correlated with CHO-K1 cell growth (Klanert et al, 2016) and corroborates miR-29's repressive functional role in cells (Garzon et al, 2009; Kwon et al, 2014; Mott et al, 2007; Xiong et al, 2010). Earlier we reported that 4-OHT increased miR-29b-1/a expression in LY2 endocrine-resistant breast cancer cells based on microarray analysis of miRNA expression (Manavalan et al, 2011) and recently confirmed this observation by qPCR (Muluhngwi et al, 2017). In addition, we observed that 4-OHT increased pri-miR-29b-1/a transcription in an ERα-dependent manner in LCC9 and LY2 cells (Muluhngwi et al, 2017).…”

“…Earlier we reported that 4-OHT increased miR-29b-1/a expression in LY2 endocrine-resistant breast cancer cells based on microarray analysis of miRNA expression (Manavalan et al, 2011) and recently confirmed this observation by qPCR (Muluhngwi et al, 2017). In addition, we observed that 4-OHT increased pri-miR-29b-1/a transcription in an ERα-dependent manner in LCC9 and LY2 cells (Muluhngwi et al, 2017). Thus, the 4-OHT stimulation of miR-29b-1/a in the CHO-K1 cells resembles that seen in the endocrine-resistant LCC9 and LY2 breast cancer cells.…”

Assessment of the Diagnostic Potential of miR-29a-3p and miR-92a-3p as Circulatory Biomarkers in Acute Myeloid Leukemia

“…Similar Results were reported by other study groups (Zhu et al, 2013;Gong et al, 2014;Xu et al, 2014) who reported a downregulation in miR-29a/29b levels in peripheral blood mononuclear cells and bone marrow from AML patients compared with healthy individuals. Also, miR-29a was found to be downregulated in many other types of neoplasms like lung cancer (Barkley and Santocanale, 2013), oral squamous carcinoma (Lu et al, 2014), glioblastoma (Xi et al, 2017), metastatic prostate cancer (Ahmed et al, 2013), ALK-positive anaplastic large cell lymphomas (Desjobert et al, 2011), endocrine-sensitive breast cancer (Muluhngwi et al, 2017).…”

Targeting of TLE3 by miR‑3677 in human breast cancer promotes cell proliferation, migration and invasion

“…Compelling evidence has indicated that miRNAs are novel modulators of cancer progression and novel targets for cancer therapy, including BC treatment (9)(10)(11). miR-137 was reported to suppress the cell growth of BC by reducing the levels of epidermal growth factor receptor (12).…”