MiR-873 regulates ERα transcriptional activity and tamoxifen resistance via targeting CDK3 in breast cancer cells

Abstract

miRNAs (microRNAs) are frequently and aberrantly expressed in many cancers. MiR-873 has been revealed to be downregulated in colorectal cancer and glioblastoma. However, its function remains unclear. Here we report that miR-873 is downregulated in breast tumor compared with normal tissue. Enforced expression of miR-873 decreases the transcriptional activity of ER (estrogen receptor)-α but not ERβ through the modulation of ERα phosphorylation in ER-positive breast cancer cells. We also found that miR-873 inhibits breast cancer cell proliferation and tumor growth in nude mice. Reporter gene assays revealed cyclin-dependent kinase 3 (CDK3) as a direct target of miR-873. CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3. Interestingly, miR-873 was observed to be downregulated in tamoxifen-resistant MCF-7/TamR cells, while CDK3 is overexpressed in these cells. More importantly, re-expression of miR-873 reversed tamoxifen resistance in MCF-7/TamR cells. Our data demonstrate that miR-873 is a novel tumor suppressor in ER-positive breast cancer and a potential therapeutic approach for treatment of tamoxifen-resistant breast cancer.

MicroRNA-873 Promotes Cell Proliferation, Migration, and Invasion by Directly Targeting TSLC1 in Hepatocellular Carcinoma

“…In recent years, many miRNAs have been recognized to promote progression of HCC through enhancing oncogene expression or inhibiting tumor suppressor genes [10-12]. miRNA-873 has been reported to be frequently and aberrantly expressed in many cancers, such as glioblastoma [13], lung adenocarcinoma [14], breast cancer [15] and ovarian cancer [16]. miRNA-873 inhibits ER (estrogen receptor)-α activity and cell growth by targeting CDK3, mediating tamoxifen resistance [15].…”

“…miRNA-873 has been reported to be frequently and aberrantly expressed in many cancers, such as glioblastoma [13], lung adenocarcinoma [14], breast cancer [15] and ovarian cancer [16]. miRNA-873 inhibits ER (estrogen receptor)-α activity and cell growth by targeting CDK3, mediating tamoxifen resistance [15]. miRNA-873 is downregulated in glioblastoma, inhibiting cell proliferation, migration and invasion and inducing apoptosis through suppressing the expression of IGF2BP1 [13].…”

MiR-203 inhibits estrogen-induced viability, migration and invasion of estrogen receptor α-positive breast cancer cells

“…These findings suggest that certain miRs are involved in the development of breast cancer. Indeed, some miRs have been demonstrated to act as oncogenes or tumor suppressors in breast cancer (25)(26)(27). For instance, miR-29b was previously found to be significantly downregulated in breast cancer, associated with poorer disease-free survival, and was suggested to be an independent prognostic factor for overall survival (28).…”

Roles for miRNAs in endocrine resistance in breast cancer

“…ERα is regulated by post-translational modifications including phosphorylation, methylation, sumoylation, and palmitoylation (Acconcia, et al 2004; Cui, et al 2014; Li, et al 2003; Sentis, et al 2005; Zhang, et al 2013). These modifications influence ERα interaction with other molecules, including transcriptional coregulators, hence regulating gene transcription (Figure 1).…”