Search

Triple negative breast cancer (TNBC) has higher aggressiveness and poorer outcomes compared with other subtypes of breast cancer. However, the genomic and molecular aberrations of TNBC are largely unknown. In this study, miR-374a-5p was discovered as a novel TNBC-specific miRNA and its functions and the molecular mechanisms involved were investigated. Combined gene expression profiling of miRNA-microarray and human transcriptome dataset analysis revealed that miR-374a-5p is specifically upregulated in TNBC patients. Functional studies using in vitro and in vivo models indicated that upregulated miR-374a-5p promotes tumor progression in TNBC. miR-374a-5p was also found to directly target arrestin beta 1 (ARRB1) that is specifically downregulated in TNBC patients in several human genomic datasets. Overexpressed ARRB1 reduced TNBC cell growth and migration, and the ARRB1 expression level is inversely correlated with the histological grade of the breast cancer and positively associated with TNBC patient survival, suggestive of a tumor-suppressive function of ARRB1 in breast cancer. Interestingly, increased ARRB1 activates AMPK in TNBC cells, associated with the expression of miR-374a-5p. Taken together, the findings suggest that miR-374a-5p is a potential prognostic marker of TNBC.

Lymphocyte antigen 6 family member K (LY6K) is upregulated in a number of types of cancer and promotes tumor cell proliferation and metastasis. In addition, LY6K is involved in tamoxifen resistance in breast cancer. However, the in vivo molecular mechanism of LY6K has not yet been investigated. In the present study, transgenic mice overexpressing human LY6K (hLY6K) were generated using the pMAMneo vector, and the effect of LY6K upregulation in vivo was investigated. A total of 4 transgenic mice were generated, and the gene copy number was examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RT-qPCR demonstrated that mRNA of hLY6K was overexpressed in the thymus and spleen of the transgenic mice compared with wild-type mice. Flow cytometric analysis demonstrated that the proportions of B and T cells in the spleen were similar in wild-type and transgenic mice; however, the proportion of thymic mature T cells decreased in the transgenic mice, while there was an increase in the proportion of naïve T cells. These findings suggest that the overexpression of LY6K suppresses T cell development, and that LY6K is a potential therapeutic target for cancer.

Estrogen receptor-alpha is a clinically important therapeutic target for breast cancer. However, tumors that lose ERα are less responsive to anti-estrogens such as tamoxifen. MicroRNAs are small RNAs that regulate expression of their target gene and dysregulations of miRNA has been identified in many diseases including human cancer. However, only a few miRNAs associated with tamoxifen resistance has been reported. In this study, we found that lymphocyte antigen 6 complex, which is a member of the Ly-6/μPAR superfamily and related to breast cancer progression and metastasis, is inversely correlated with ERα expression. We, for the first time, found miRNAs involved in the regulatory molecular mechanism between ERα and LY6K and related to tamoxifen susceptibility in breast cancer. miR-192-5p, induced by LY6K, downregulates ERα directly and induced tamoxifen resistance in ERα-positive breast cancer cells. In addition, re-expression of ERα in ERα-negative breast cancer cells increased miR-500a-3p expression and directly inhibits LY6K expression. Ectopic expression of miR-500a-3p sensitized ERα-negative cells to tamoxifen by increasing apoptosis. Finally, we observed an inverse correlation between LY6K and ERα in primary breast cancer samples. We found that patients with recurrence showed high expression of miR-192-5p after tamoxifen treatments. In addition, expression of miR-500a-3p was significantly correlated to survival outcome. As miRNAs involved in the regulatory mechanism between LY6K and ERα can affect tamoxifen resistance, downregulating miR-192-5p or re-expressing miR-500a-3p could be a potential therapeutic approach for treating tamoxifen resistant patients. Citation Format: Yesol Kim, Dasom Son, Kyung Hyun Yoo, Jong Hoon Park. miRNAs involved in LY6K and estrogen receptor-α contribute to tamoxifen susceptibility in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 482. doi:10.1158/1538-7445.AM2017-482