The present study demonstrated that the expression of miR-342 in the ERα-positive breast cancer tumors and cells was significantly greater than that in the ERα-negative breast cancer tumors and cells. The study reported for the first time that the levels of miR-342 expression were positively correlated with ERα mRNA expression and also revealed a correlation between increased tamoxifen sensitivity and the elevated levels of ERα mRNA by augmenting the miR-342 expression.
In experimental models, a single miRNA is able to regulate a number of genes (19
). It has been reported that miR-22 is downregulated in ERα-positive human breast cancer cell lines and clinical samples (13
). miR-22 inhibits estrogen signaling by directly targeting the ERα mRNA (12
). miR-221/222 negatively regulates ERα and is associated with tamoxifen resistance in breast cancer (14
). Previous studies have shown that miR-342 is an ERα-associated miRNA (8
). The results of the present study show that the expression levels of miR-342 were markedly higher in the ERα-positive breast cancer tumors than in the ERα-negative tumors and that the levels of miR-342 gradually increased as ERα mRNA expression increased, suggesting that miR-342 is a key factor for the regulation of ERα expression in the development and progression of human breast cancer.
Endocrine therapy has become the most significant treatment option for women with ERα-positive breast cancer, with ~70% of primary breast cancers expressing ERα. The selective ERα modulator tamoxifen is the most commonly prescribed endocrine therapy. Currently there are only a few useful tumor markers to guide management decisions for women with ERα-positive breast tumors. Cittelly et al
) demonstrated that miR-342 was markedly suppressed in multiple tamoxifen-resistant breast tumor cell lines and in primary breast tumors of patients whose tamoxifen therapy failed. Significantly, the reintroduction of miR-342 sensitized the refractory breast tumor cells to tamoxifen therapy, suggesting that miR-342 is a significant regulator of the tamoxifen response. In the present study, miR-342 expression was shown to be positively correlated with the expression of ERα in human breast cancer tissues and the introduction of miR-342 into estrogen-dependent breast cancer cells was shown to upregulate ERα expression and enhance tamoxifen sensitivity with decreased cellular proliferation and increased apoptosis. By contrast, inhibition of miR-342 in the MCF-7 cells downregulated the ERα expression and weakened the response to tamoxifen, with increased cellular proliferation and decreased apoptosis. Based on these observations, we propose that the levels of miR-342 expression that correspond to the ERα mRNA expression locus may act as a biomarker for tamoxifen sensitivity in ERα-positive breast cancer.
Cittelly et al
) reported that there was no evident association between the direct targets of miR-342 and the tumor cell response to tamoxifen. Ingenuity Pathway Analysis of the entire set of genes significantly altered by miR-342 revealed a significant association between the miR-342-regulated genes and cell apoptosis. This result is consistent with the observations of the present study that showed that ectopic miR-342 expression sensitized MCF-7 cells to tamoxifen-induced apoptosis. Similarly, miR-342 expression in colorectal cancer cells results in tumor cell apoptosis (20
). Nevertheless, the activity of miR-342 appears to differ functionally in colorectal and breast tumor cells. The results of the present study indicated that miR-342 expression alone was not sufficient to induce cell death, but that miR-342 sensitizes cells to cellular proliferation inhibition and apoptosis associated with tamoxifen exposure.
In addition, the results showed that the levels of miR-342 expression increased in VEGF-negative, HER2-negative and Luminal-A breast cancer samples. As the VEGF-negative, HER2-negative and Luminal-A signals indicate a good prognosis, miR-342 may be a biomarker of predicting a good prognosis for breast cancer.
In conclusion, the present data indicated for the first time that miR-342 expression is positively correlated with the expression of ERα mRNA in human breast cancer tissues and that the introduction of miR-342 into estrogen-dependent breast cancer cells enhances tamoxifen sensitivity. miR-342 may be a novel candidate for ERα-specific endocrine therapy in breast cancer.