Abstract 144: MicroRNA-190, regulated by estrogen receptor signaling, suppresses expression of the metastasis-promoting gene PAR-1 and is associated with breast cancer progression

Abstract

Abstract Cancer metastasis contributes to mortality of breast cancer patients. The present study, based on the fundamental concept that dissociation of the extracellular matrix is the driving force for tumor metastasis, was performed to examine the hypothesis that microRNA-190 (miR-190) is important in regulating breast cancer metastasis by decreasing the expression of protease-activated receptor-1 (PAR-1), a gene encoding a receptor for matrix metalloproteinase1 and thrombin that is associated with tumor metastasis. This hypothesis was initially suggested by the observations that the expression of a reporter gene could be regulated by a specific sequence in the 3′-untranslated region of PAR-1 and that miR-190 was complementary to this sequence. Support for our hypothesis came from the findings that (a) PAR-1 expression was directly inhibited by miR-190, (b) increased miR-190 expression suppressed cell migration and invasiveness, and (c) the level of miR-190 expression in primary breast carcinomas correlated with overall survival. Interestingly, we defined the promoter region of miR-190 and noted that it contained half of an estrogen receptor (ER) response element, supporting the breast tumorigenic contribution of miR-190. This was further confirmed by the findings that miR-190 expression was activated by 17β-estradiol and that the ER bound directly to this promoter and regulated miR-190 expression. The findings of the present study may explain why ER-positive patients usually have a favorable progression and how ER regulates cancer metastasis, i.e. ER signaling regulates miR-190 expression, thus causing suppression of PAR-1 expression, resulting in inhibition of breast cancer metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 144. doi:1538-7445.AM2012-144