Abstract 1437: Coordinate regulation of miR-183-96-182 and miR10b by Breast Cancer Metastasis Suppressor 1 results in a decrease in migration and invasion of metastatic breast cancer cells
Authors: Stewart Mark D. , Edmonds Mick D. , Powers J Kent , Hurst Douglas R. , Welch Danny R. 
Published: June 2012

To date more than 30 metastasis suppressors have been identified by functional assays. BReast cancer Metastasis Suppressor 1 (BRMS1) suppresses metastasis of multiple tumor types by hindering the ability to colonize ectopic tissues without blocking tumorigenesis. BRMS1 interacts with SIN3:histone deacetylase complexes which can lead to metastasis suppression through epigenetic regulation of metastasis-associated gene transcription. In addition to regulating protein-coding genes (EGFR, OPN, TWIST), we showed that BRMS1 coordinately regulates metastasis-associated miRNA, e.g., increases metastasis-suppressing miRNA (miR-183-96-182, miR-146a/b, miR-335) and decreases metastasis-promoting miRNA (miR-10b, miR-373, miR-520c). We also observed significant upregulation of miR-96, which is part of the miR-183-96-182 cluster (miR-183C). In this study, we hypothesized that miR-96 could inhibit metastasis-associated processes and that restoration of miR-10b expression in BRMS1-expressing cells would restore metastatic efficiency. Over-expression of miR-96 (and individual miRNA within miR-183C) in metastatic MDA-MB-231 (231) breast cancer cells decreased invasion (∼50%) and migration (∼40%). Knockdown of individual miRNA in 231 or MDA-MB-435 (435) cells expressing BRMS1 (231B; 435B) increased motility, migration, and invasion in vitro (P&lt;0.05). Pilot in vivo metastasis assays showed a trend toward decreased metastasis with miR-183C components, but fully powered studies are underway. Re-expression of miR-10b in 231B cells partially restored motility and invasion in vitro (P&lt;0.02) but the effect on metastasis, while not statistically significant, did modestly increase. These results are consistent with the hypothesis that metastamiR are downstream mediators of BRMS1 metastasis suppression; however, coordinated expression changes are necessary to achieve significant in vivo biological effects. Given that over-expression of individual miR-183C components leads to nearly identical suppression of migration and invasion, we asked whether exogenous over-expression of one of the miR-183C miRNA affected expression of the other endogenous miR-183C miRNA (e.g., Does miR-96 over-expression change miR-182 or miR-183 expression?). Ectopic expression of individual miR-183C members led to increased expression of the other miRNA within the cluster. These findings imply feedback mechanisms for miRNA within miR-183C which may explain discordant data in other cancers where miR-183C exerted tissue-selective metastasis-promoting or -suppressing actions. The linked expression of miRNA within a cluster advise caution when designing and interpreting results from a single miRNA.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1437. doi:10.1158/1538-7445.AM2011-1437