Altered MicroRNA Activity Promotes Resistance to Endocrine Therapy
Abstract
MicroRNAs (miRNAs) have tumor suppressive and oncogenic potential in human cancer, but little is known about the extent at which miRNA expression is modified after anti-estrogen treatment and the contribution of specific miRNAs to the acquisition of anti-estrogen resistance. To answer this question, in Aim 1, we performed miRNA profiling of tamoxifen-resistant and sensitive breast cancer cells treated with Estradiol or Tam. Several miRNAs were intrinsically downregulated in tam-resistant cells or were deregulated after treatments, suggesting that endocrine signaling can modulate miRNA expression. One miRNA sensitized resistant cells to tam-induced apoptosis and may emerge as a potential therapeutic target to sensitize endocrine refractory breast tumors. In Aim 2, we tested the hypothesis that regulation of miRNAs involved in modulating anti-apoptotic BCL-2 plays a role in tamoxifen resistance in breast cancer cell lines. Equivalent levels of BCL-2 mRNA were observed in tam-sensitive and resistant cells; however, tam-resistant MCF-7D16 cells upregulated BCL-2 protein and expressed reduced levels of BCL-2 targeting miRNAs miR15a and miR16. Reintroduction of miR15a/16 reduced taminduced BCL-2 expression and sensitized MCF-7D16 to tam. Conversely, suppression of miR15a/16 activated BCL-2 expression and rendered cells tam-resistant. In conclusion, miRNAs constitute a novel mechanism for endocrine-therapy evasion and provides a template for unique therapeutic interventions involving modulation of miRNAs in combination with tamoxifen.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2009
- Accession Number
- ADA509771
Entities
People
- Diana M Cittelly
Organizations
- University of Colorado Boulder