The Role of MicroRNAs in Estrogen Receptor α-Positive Human Breast Cancer

MicroRNAs (miRNAs) are a class naturally occurring small non-coding RNAs that control gene expression by targeting mRNAs for translational repression or cleavage (Krol et al., 2010). Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers, and that lossor gain-of function of specific miRNAs contributes to breast epithelial cellular transformation and tumorigenesis (Esquela-Kerscher et al., 2006). miRNA expression profiling also revealed that miRNAs are differently expressed among molecular subtypes in breast cancer (Blenkiron et al., 2007; Iorio et al., 2005). There are large-scale molecular differences between estrogen receptor (ER) ┙-positive and ER┙-negative breast cancers (Perou et al., 2000; Sorlie et al., 2003). Endocrine therapy has become the most important treatment option for women with ER┙-positive breast cancer, and approximately 70% of primary breast cancers express ER┙. ER┙ is essential for estrogen-dependent growth, and its level of expression is a crucial determinant of response to endocrine therapy and prognosis in ER┙-positive breast cancer (Dowsett et al., 2008; Harvey et al., 1999; Yamashita et al., 2006). Multiple mechanisms involved in altering ER┙ gene expression in breast cancer have been proposed, including ER┙ gene amplification (Holst et al., 2007) as well as transcriptional silencing by DNA methylation of CpG islands within the ER┙ promoter (Giacinti et al., 2006) and mutations within the open reading frame of ER┙ (Herynk et al., 2004). However, expression levels of ER┙ in breast cancer tissues differ widely among patients (Yamashita et al., 2011), and frequently change during disease progression and in response to systemic therapies (Yamashita et al., 2009). It was reported that the microRNA miR-206 decreases endogenous ER┙ mRNA and protein levels in human MCF-7 breast cancer cells via two specific target sites within the 3’-untranslated region (UTR) of the human ER┙ transcript (Adams et al., 2007). We found that the expression levels of miR-206 were gradually decreased as ER┙ protein expression increased in breast cancer tissues, suggesting that miR-206 is a key factor for the regulation of ER┙ expression in human breast cancer (Kondo et al., 2008). Moreover, recent studies have shown that ER┙regulating miRNAs, miR-18a, miR-18b, miR-22, miR-193b, miR-302c, and miR-221/222, as well as miR-206, directly targeted ER┙ in 3’UTR reporter assays, and suggested that several miRNAs regulate ER┙ expression.