Pluripotent stem cell miRNAs and metastasis in invasive breast cancer.

Volinia S, Nuovo G, Drusco A, Costinean S, Abujarour R, Desponts C, Garofalo M, Baffa R, Aeqilan R, Maharry K, Garzon ME, Di Leva G, Gasparini P, Dama P, Marchesini J, Galasso M, Manfrini M, Zerbinati C, Corrà F, Wise T, Wojcik SE, Previati M, Pichiorri F, Zanesi N, Alder H, Palatini J, Huebner KF, Shapiro CL, Negrini M, Vecchione A, Rosenberg AL, Croce CM, Volinia S, Nuovo G, Drusco A, Costinean S, Abujarour R, Desponts C, Garofalo M, Baffa R, Aeqilan R, Maharry K, Sana ME, Garzon ME, Di Leva G, Gasparini P, Dama P, Marchesini J, Galasso M, Manfrini M, Zerbinati C, Corrà F, Wise T, Wojcik SE, Previati M, Pichiorri F, Zanesi N, Alder H, Palatini J, Huebner KF, Shapiro CL, Negrini M, Vecchione A, Rosenberg AL, Croce CM, Garzon R
J Natl Cancer Inst 106 12/01/2014

Abstract

BACKGROUND: The purpose of this study is to determine whether microRNA for pluripotent stem cells are also expressed in breast cancer and are associated with metastasis and outcome.

METHODS: We studied global microRNA profiles during differentiation of human embryonic stem cells (n =26) and in breast cancer patients (n = 33) and human cell lines (n = 35). Using in situ hybridization, we then investigated MIR302 expression in 318 untreated breast cancer patients (test cohort, n = 22 and validation cohort, n = 296). In parallel, using next-generation sequencing data from breast cancer patients (n = 684), we assessed microRNA association with stem cell markers. All statistical tests were two-sided.

RESULTS: In healthy tissues, the MIR302 (high)/MIR203 (low) asymmetry was exclusive for pluripotent stem cells. MIR302 was expressed in a small population of cancer cells within invasive ductal carcinoma, but not in normal breast (P < .001). Furthermore, MIR302 was expressed in the tumor cells together with stem cell markers, such as CD44 and BMI1. Conversely, MIR203 expression in 684 breast tumors negatively correlated with CD44 (Spearman correlation, Rho = -0.08, P = .04) and BMI1 (Rho = -0.11, P = .004), but positively correlated with differentiation marker CD24 (Rho = 0.15, P < .001). Primary tumors with lymph node metastasis had cancer cells showing scattered expression of MIR302 and widespread repression of MIR203. Finally, overall survival was statistically significantly shorter in patients with MIR302-positive cancer cells (P = .03).

CONCLUSIONS: In healthy tissues the MIR302(high)/MIR203(low) asymmetry was characteristic of embryonic and induced pluripotency. In invasive ductal carcinoma, the MIR302/MIR203 asymmetry was associated with stem cell markers, metastasis, and shorter survival.

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