miR-221/222 control luminal breast cancer tumor progression by regulating different targets.

Abstract

α6β4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between β4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different β4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express β4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates β4 expression. We demonstrate that miR-221/222 overexpression results in β4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving β4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for β4 integrin 3'UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven β4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted "normal" breast epithelial cells, indicating that the mechanism is cancer cell-specific.   These results provide the first evidence of a post-transcriptional mechanism that regulates β4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy.

• Authors: Patrizia Dentelli, Matteo Traversa, Arturo Rosso, Gabriele Togliatto, Cristina Olgasi, Caterina Marchiò, Paolo Provero, Antonio Lembo, Giulia Bon, Laura Annaratone, Anna Sapino, Rita Falcioni, Maria Felice Brizzi
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 13 Issue 11 Pg. 1811-26 ( 2014) ISSN: 1551-4005 [Electronic] United States
• PMID: 24736554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Integrin beta4
• Ki-67 Antigen
• MIRN221 microRNA, human
• MIRN222 microRNA, human
• MicroRNAs
• RNA, Small Interfering
• STAT5 Transcription Factor
• STAT5A protein, human
• Tumor Suppressor Proteins
• Luciferases
• ADAM Proteins
• ADAM17 Protein
• ADAM17 protein, human

Topics

• ADAM Proteins (genetics, metabolism)
• ADAM17 Protein
• Analysis of Variance
• Breast Neoplasms (metabolism, physiopathology)
• Carcinoma, Ductal, Breast (metabolism, physiopathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• DNA Primers (genetics)
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic (physiology)
• Gene Silencing
• Humans
• Immunohistochemistry
• Integrin beta4 (metabolism)
• Ki-67 Antigen (metabolism)
• Luciferases
• MicroRNAs (metabolism)
• Neoplasm Invasiveness (genetics)
• RNA, Small Interfering (genetics)
• STAT5 Transcription Factor (metabolism)
• Tumor Suppressor Proteins (metabolism)