TGF-β upregulates miR-181a expression to promote breast cancer metastasis
Molly A. Taylor, … , David Danielpour, William P. Schiemann
Molly A. Taylor, … , David Danielpour, William P. Schiemann
Published December 17, 2012
Citation Information: J Clin Invest. 2013;123(1):150-163. https://doi.org/10.1172/JCI64946.
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Research Article Oncology

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.

Authors

Molly A. Taylor, Khalid Sossey-Alaoui, Cheryl L. Thompson, David Danielpour, William P. Schiemann

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Figure 6

Inhibition of miR-181a abrogates pulmonary tumor outgrowth and increases survival in mice.

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Inhibition of miR-181a abrogates pulmonary tumor outgrowth and increases...
(A and B) The ability of TGF-β1 (5 ng/ml) to suppress 4T1 organoid growth was abrogated by elevated miR-181a activity (A), while basal 4T1 organoid growth was significantly suppressed by miR-181a inactivation (B). Data are the mean ± SEM of bioluminescent signals obtained in 3 independent experiments completed in triplicate. *P < 0.05, Student’s t test. Original magnification, ×20. (C) Luciferase-expressing 4T1 cells engineered to stably express an miR-181a antagonist (i.e., miArrest 181a) were injected into the lateral tail veins of BALB/c mice (n = 5), and pulmonary tumor outgrowth was monitored by intravital bioluminescent imaging. Data are the mean ± SEM of pulmonary photon flux readings 24 days after injection, while the inset shows representative bioluminescent signals of pulmonary outgrowth measured on day 24. *P < 0.05. (D) Kaplan–Meier survival curves of BALB/c mice (n = 5) from C.