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Evaluation of the expression and role of miRNAs 221, 222 e 4728-3p in cancer stem-cells derived from Her2+ breast cancer cell lines

Grant number: 11/19784-6
Support type:Regular Research Grants
Duration: March 01, 2012 - February 28, 2015
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal researcher:Emmanuel Dias-Neto
Grantee:Emmanuel Dias-Neto
Home Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
Assoc. researchers:Diana Noronha Nunes

Abstract

A small population of breast tumor cells, denominated tumor-initiating cells or cancer stem-cells (CSCs), is highly tumorigenic when injected into immunodeficient mice. These CSCs, which are characterized by positive CD44 expression and low or undetectable levels of CD24 (CD44+CD24/low), contribute to tumor metastasis as well as to treatment resistance. Some miRNAs are differentially expressed in stem cells, suggesting their role in stem cell regulation. Previous studies have shown miRNA-221 and miRNA-222 to be up-regulated in breast CSCs when compared to differentiated cells, and the recently discovered miR-4728-3p, located in an intron of Her2, is significantly overexpressed in Her2+ tumors and cell lines. In this project, we aim to contribute to a better understanding of the biology of Her2+ breast cancer cell-line-derived CSCs, including the role of miR-221/222 and 4728-3p in these cells. For that, breast cancer cell-lines will be grown in conditions that induce the formation of mamospheres, which are spheroid cell structures enriched in CSCs with low differentiation, low apoptosis and other stem-cell properties, such as the expression of OCT-4, NANOG and SOX2. After inducing or blocking the expression of miR-221, -222 and -4728-3p, the mamosphere-formation efficiency (MFE), self-renewal and stem-cell maintenance capabilities of the cell lines will be evaluated. The migration and invasion capabilities of the cells, and how these features are affected by the expression of miR-221/222 and 4728-3p will also be investigated, together with the experimental identification of putative miRNA gene-targets, using a large-scale DNA sequencing approach. (AU)