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Altered MicroRNA Activity Promotes Resistance to Endocrine Therapy

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Final rept. 1 Jul 2008-30 Jun 2009

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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 miR15a16 reduced taminduced BCL-2 expression and sensitized MCF-7D16 to tam. Conversely, suppression of miR15a16 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.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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