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Pluripotent Stem Cell miRNAs and Metastasis in Invasive Breast Cancer.

By: Stefano Volinia, Gerard Nuovo, Alessandra Drusco, Stefan Costinean, Ramzey Abujarour, Caroline Desponts, Michela Garofalo, Raffaele Baffa, Rami Aeqilan, Kati Maharry, Maria Elena Sana Ramiro Garzon, Gianpiero Di Leva, Pierluigi Gasparini, Paola Dama, Jlenia Marchesini, Marco Galasso, Marco Manfrini, Carlotta Zerbinati, Fabio Corrà, Timothy Wise, Sylwia E Wojcik, Maurizio Previati, Flavia Pichiorri, Nicola Zanesi, Hansjuerg Alder, Jeff Palatini, Kay F Huebner, Charles L Shapiro, Massimo Negrini, Andrea Vecchione, Anne L Rosenberg, Carlo M Croce

Department of Molecular Virology, Immunology and Molecular Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (SV, GN, AD, SC, MiG, RAe, RG, GDL, PG, PD, TW, SEW, FP, NZ, HA, KFH, CMC); Biosystems Analysis, LTTA, Deptartment of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy, (SV, MES, JM, MaG, MM, CZ, FC, MP, JP, MN); Fate Therapeutics, San Diego, CA (RAb); Department of Chemistry, The Scripps Research Institute, La Jolla, CA (CD); Department of Urology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA (RB); Comprehensive Cancer Center, The Ohio State University, Columbus, OH (KM); Deptartment of Internal Medicine, James Cancer Hospital and Ohio State University Comprehensive Cancer Center, The Ohio State University (CLS); Division of Pathology, II University of Rome "La Sapienza," Ospedale Santo Andrea, Rome, Italy (AV); Department of Surgery, Thomas Jefferson University Medical College, Philadelphia, PA (ALR). carlo.croce@osumc.edu.
2014-12-; doi: 10.1093/jnci/dju324

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.