MicroRNA-222 Expression as a Predictive Marker for Tumor Progression in Hormone Receptor-Positive Breast Cancer

Abstract

PurposeThe microRNA-221/222 (miR-221/222) gene cluster has been reported to be associated with the promotion of epithelial-mesenchymal transition (EMT), downregulation of estrogen receptor-α, and tamoxifen resistance in breast cancer. We studied the expression of miR-222 in human breast cancer samples to analyze its relationship with clinicopathologic features of the tumor, including estrogen receptor status, expression of EMT markers, and clinical outcomes.MethodsQuantitative real-time polymerase chain reaction was performed to detect the expression of miR-222 in 197 invasive breast cancers. Expression of EMT markers (vimentin, smooth muscle actin, osteonectin, N-cadherin, and E-cadherin) was evaluated using immunohistochemistry.ResultsHigh miR-222 levels were associated with high T stage, high histologic grade, high Ki-67 proliferation index, and HER2 gene amplification. Its expression was significantly higher in the luminal B and human epidermal growth factor receptor 2-positive (HER2+) subtypes than in the luminal A and triple-negative subtypes. In the hormone receptor-positive subgroup, there was a significant negative correlation between miR-222 and estrogen receptor expression, and miR-222 expression was associated with EMT marker expression. In the group as a whole, high miR-222 expression was not associated with clinical outcome. However, subgroup analyses by hormone receptor status revealed that high miR-222 expression was a poor prognostic factor in the hormone receptor-positive subgroup, but not in the hormone receptor-negative subgroup.ConclusionThis study showed that miR-222 is associated with down-regulation of the estrogen receptor, EMT, and tumor progression in hormone receptor-positive breast cancer, indicating that miR-222 might be associated with endocrine therapy resistance and poor clinical outcome in hormone receptor-positive breast cancer.

Sex disparity in cancer: roles of microRNAs and related functional players

“…In particular, ERβ has been reported as capable of inducing autophagy-mediated cell death both in post-mitotic cells and proliferating cells, whereas ERα has been suggested to induce proliferation in transformed cells and autophagy in post-mitotic cells [ 60 , 61 ]. Interestingly, among the number of X-linked miRs, six of them putatively bind and regulate ERα, including miR-221&222 [ 62 ]. Specifically, miR-221&222 inhibit ERα mRNA translation by direct binding to its 3ʹUTR, being in turn repressed by ERα according to a negative feedback loop [ 63 ].…”

microRNA Regulation in Estrogen Receptor-Positive Breast Cancer and Endocrine Therapy

“…In context with miR-221/222 expression and breast cancer in patients, recent reports indicate that miR-221/222 expression does not significantly correlate with overall and disease-free survival in breast cancer patients not grouped by subtype [ 30 , 31 ]. However, according to a study by Han et al (2017), high expression levels of miR-222 in patients with ER + breast cancer were significantly ( P = 0.021) associated with decreased disease-free survival as compared to ER + breast cancer patients exhibiting low levels of miR-222 [ 31 ]. In contrast, the effect of miR-222 expression was not correlated with significant differences in disease-free survival of ER − breast cancer patients.…”

Overexpression of miR-222-3p promotes proliferation and inhibits apoptosis in diffuse large B-cell lymphoma cells via suppressing PPP2R2A

“…7,8 As a member of miRNAs, miR-222 has been proved to participate in the process of multiple diseases such as breast cancer, nasopharyngeal carcinoma and colorectal cancer. [9][10][11] A previous study indicates that the intestinal inflammation can be aggravated by up-regulation of miR-222 during the disease progression. 12 Importantly, there is a strong relationship between miR-222 and the development of DLBCL.…”