TGF-β upregulates miR-181a expression to promote breast cancer metastasis

Abstract

Late-stage breast cancer metastasis is driven by dysregulated TGF-β signaling, but the underlying molecular mechanisms have not been fully elucidated. We attempted to recapitulate tumor and metastatic microenvironments via the use of biomechanically compliant or rigid 3D organotypic cultures and combined them with global microRNA (miR) profiling analyses to identify miRs that were upregulated in metastatic breast cancer cells by TGF-β. Here we establish miR-181a as a TGF-β-regulated "metastamir" that enhanced the metastatic potential of breast cancers by promoting epithelial-mesenchymal transition, migratory, and invasive phenotypes. Mechanistically, inactivation of miR-181a elevated the expression of the proapoptotic molecule Bim, which sensitized metastatic cells to anoikis. Along these lines, miR-181a expression was essential in driving pulmonary micrometastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice. Finally, miR-181a expression was dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and was highly predictive for decreased overall survival in human breast cancer patients. Collectively, our findings strongly implicate miR-181a as a predictive biomarker for breast cancer metastasis and patient survival, and consequently, as a potential therapeutic target in metastatic breast cancer.

PTPN2 attenuates T-cell lymphopenia-induced proliferation

“…Interestingly, recent studies have shown that TGFb can upregulate the expression of miRNA-181a in metastatic breast cancer cells 58 . Our studies demonstrate that heterozygous PTPN2 deficiency in naive CD8 þ T cells is sufficient to augment CD8 þ T-cell LIP in irradiated hosts.…”

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

“…miR-181a: Late-stage BC metastasis is driven by dysregulated transforming growth factor β (TGFβ) signaling (69). In 3D organotypic cultures, miR-181a is up-regulated by TGFβ and inactivation of miR-181a attenuates TGFβ-mediated EMT, invasion and migration (70). Pro-apoptotic protein Bim was identified as one of the targets of miR-181a, resulting in decrease of anoikis after inhibition by miR-181a (71).…”

“…Pro-apoptotic protein Bim was identified as one of the targets of miR-181a, resulting in decrease of anoikis after inhibition by miR-181a (71). Inactivation of miR-181a in 4T1 cells impaired their ability to grow as 3D organotypic cultures (70). In an experimental metastasis model, inhibition of miR-181a in 4T1 cells decreased pulmonary tumor burden and increased survival time (70).…”

“…Inactivation of miR-181a in 4T1 cells impaired their ability to grow as 3D organotypic cultures (70). In an experimental metastasis model, inhibition of miR-181a in 4T1 cells decreased pulmonary tumor burden and increased survival time (70). In an orthotopic fat pad injection-based metastasis model, miR-181a was essential for pulmonary metastatic outgrowth of 4T1 cells (70).…”

“…In an experimental metastasis model, inhibition of miR-181a in 4T1 cells decreased pulmonary tumor burden and increased survival time (70). In an orthotopic fat pad injection-based metastasis model, miR-181a was essential for pulmonary metastatic outgrowth of 4T1 cells (70). Regarding clinical prognostic relevance, miR-181a was shown to be selectively up-regulated in metastatic BC, particularly in TNBC and upregulation was highly predictive for overall survival in BC patients (70).…”