Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status.
The sole overexpression of pivotal regulators of the embryonic Epithelial-Mesenchymal Transition (EMT) genetic program ("EMT status") may be sufficient to efficiently drive the ontogeny of the breast cancer stem cell molecular signature independently of changes in EMT functioning ("EMT phenotype"). Using basal-like breast cancer models naturally enriched in either CD44(pos)CD24(low/neg) or CD44(pos)CD24(pos) tumor-initiating cell populations we herein illustrate that non-cytotoxic concentrations of the anti-diabetic drug metformin efficiently impedes the ontogeny of generating the stem cell phenotype by transcriptionally repressing the stem cell property EMT. Metformin treatment dynamically regulated the CD44(pos)CD24(neg/low) breast cancer stem cell immunophenotype, transcriptionally reprogrammed cells through decreased expression of key drivers of the EMT machinery including the transcription factors ZEB1, TWIST1 and SNAI2 (Slug) and the pleiotrophic cytokines TGFβs, and lastly impeded the propensity of breast cancer stem cells to form multicellular "microtumors" in non-adherent and non-differentiating conditions (i.e., "mammospheres"). These findings, altogether, provide strong motivation for the continued molecular understanding and clinical development of metformin as a non-toxic therapeutic aimed to interdict the breast cancer stem cell phenotype by targeting EMT, a molecular process that is central to the ontogenesis of the breast cancer stem cell molecular signature.
Vazquez-Martin
Alejandro
A
Catalan Institute of Oncology (ICO), Girona, Catalonia, Spain.
Oliveras-Ferraros
Cristina
C
Cufí
Silvia
S
Del Barco
Sonia
S
Martin-Castillo
Begoña
B
Menendez
Javier A
JA
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D014158:Transcription, Genetic / Q000187:drug effects
D051927:CD24 Antigen; D018960:Hyaluronan Receptors; D007004:Hypoglycemic Agents; D008687:Metformin