By promoting cell differentiation, miR-100 sensitizes basal-like breast cancer stem cells to hormonal therapy

Annalisa Petrelli; Rosachiara Carollo; Marilisa Cargnelutti; Flora Iovino; Maurizio Callari; Daniela Cimino; Matilde Todaro; Laura Rosa Mangiapane; Alessandro Giammona; Adriana Cordova; Filippo Montemurro; Daniela Taverna; Maria Grazia Daidone; Giorgio Stassi; Silvia Giordano

doi:10.18632/oncotarget.2962

By promoting cell differentiation, miR-100 sensitizes basal-like breast cancer stem cells to hormonal therapy

Oncotarget. 2015 Feb 10;6(4):2315-30. doi: 10.18632/oncotarget.2962.

Authors

Affiliations

¹ University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS, Str. Provinciale, Candiolo, Torino, Italy.
² Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
³ Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
⁴ Molecular Biotechnology Center (MBC), Department of Oncological Sciences, Center for Molecular Systems Biology, Via Nizza, University of Torino, Torino, Italy.

Abstract

Basal-like breast cancer is an aggressive tumor subtype with a poor response to conventional therapies. Tumor formation and relapse are sustained by a cell subset of Breast Cancer Stem Cells (BrCSCs). Here we show that miR-100 inhibits maintenance and expansion of BrCSCs in basal-like cancer through Polo-like kinase1 (Plk1) down-regulation. Moreover, miR-100 favors BrCSC differentiation, converting a basal like phenotype into luminal. It induces the expression of a functional estrogen receptor (ER) and renders basal-like BrCSCs responsive to hormonal therapy. The key role played by miR-100 in breast cancer free-survival is confirmed by the analysis of a cohort of patients' tumors, which shows that low expression of miR-100 is a negative prognostic factor and is associated with gene signatures of high grade undifferentiated tumors. Our findings indicate a new possible therapeutic strategy, which could make aggressive breast cancers responsive to standard treatments.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Agents, Hormonal / pharmacology
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Differentiation / drug effects
Cell Differentiation / genetics*
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Kaplan-Meier Estimate
MCF-7 Cells
Mice, Inbred NOD
Mice, SCID
MicroRNAs / genetics*
Middle Aged
Neoplastic Stem Cells / metabolism*
Polo-Like Kinase 1
Prognosis
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Receptors, Estrogen / genetics
Receptors, Estrogen / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tamoxifen / pharmacology
Transplantation, Heterologous

Substances

Antineoplastic Agents, Hormonal
Cell Cycle Proteins
MIRN100 microRNA, human
MicroRNAs
Proto-Oncogene Proteins
Receptors, Estrogen
Tamoxifen
Protein Serine-Threonine Kinases