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MicroRNA Sequencing of Long-Term Estrogen Deprived Breast Cancer Cells Reveals a Potential Role for miR-181a in Estrogen-Independent Growth
Hayes, Erin
Hayes, Erin
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Abstract
Breast cancer is a genetically complex disease that affects over 230,000 people in the U.S. every year. Estrogen signaling has been shown to play a large role in the development and progression of breast tumors that express the estrogen receptor (ER). Thus, aromatase inhibitors (AIs), which prevent the synthesis of estrogen, have been increasingly valuable for the management of ER+ breast cancer. A frequent obstacle, however, is acquired resistance to AIs, characterized by heightened growth factor signaling and estrogen-independent growth. Another aspect of acquired AI resistance that is now being examined is the role of microRNA (miRNA). miRNAs are 18-22 base pair RNA molecules whose primary role is to inhibit expression of mRNA targets by inhibition of translation or by degradation of the mRNA. Here, we have conducted next-generation sequencing of the miRNAs from three breast cancer cell lines – one ER+ line that is estrogen-dependent (MCF-7), and two ER+ long-term estrogen deprived (LTED) models of estrogen-independent growth (MCF-7:5C and MCF-7:2A). We found that in the LTED MCF-7:5C and MCF-7:2A cells there were 338 and 241 miRNAs differentially expressed, respectively, compared to the MCF-7 cells. We also saw unique miRNA clusters expressed in each LTED cell line – on chromosome 14q32 in the MCF-7:5C cells and on chromosome 13q31 in the MCF-7:2A cells. Our initial in vitro work focused on the functional significance of miR-181a (overexpressed in both LTED cells). This work has shown that miR-181a is regulated by estrogen/ER signaling, that loss of miR-181a in the LTED MCF-7:5C cells has a significant effect on proliferation, and that overexpression of miR-181a increases the ability of MCF-7 cells to grow in an estrogen-deprived environment. Since our LTED MCF-7:5C cells are more sensitive to DNA damage and overexpress miR-181a, which targets BRCA1, it was surprising that these cells were not more sensitive to the PARP inhibitor olaparib, which may be explained by high basal expression of BRCA1. Overall, it is clear that the miRNA profile of estrogen-dependent breast cancer cells is unique from the estrogen-independent LTED cells, and miR-181a may have a functional role in the estrogen-independent phenotype of our LTED MCF-7:5C cells.
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Date
2015-05-31
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University of Kansas
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Keywords
Molecular biology, aromatase inhibitor, breast cancer, endocrine resistance, microRNA, miR-181a