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MicroRNA signatures predict oestrogen receptor, progesterone receptor and HER2/neu receptor status in breast cancer

Department of Surgery, Clinical Science Institute, University Hospital/National University of Ireland Galway, Galway, Ireland.
Breast cancer research: BCR (Impact Factor: 5.88). 06/2009; 11(3):R27. DOI: 10.1186/bcr2257
Source: PubMed

ABSTRACT Breast cancer is a heterogeneous disease encompassing a number of phenotypically diverse tumours. Expression levels of the oestrogen, progesterone and HER2/neu receptors which characterize clinically distinct breast tumours have been shown to change during disease progression and in response to systemic therapies. Mi(cro)RNAs play critical roles in diverse biological processes and are aberrantly expressed in several human neoplasms including breast cancer, where they function as regulators of tumour behaviour and progression. The aims of this study were to identify miRNA signatures that accurately predict the oestrogen receptor (ER), progesterone receptor (PR) and HER2/neu receptor status of breast cancer patients to provide insight into the regulation of breast cancer phenotypes and progression.
Expression profiling of 453 miRNAs was performed in 29 early-stage breast cancer specimens. miRNA signatures associated with ER, PR and HER2/neu status were generated using artificial neural networks (ANN), and expression of specific miRNAs was validated using RQ-PCR.
Stepwise ANN analysis identified predictive miRNA signatures corresponding with oestrogen (miR-342, miR-299, miR-217, miR-190, miR-135b, miR-218), progesterone (miR-520g, miR-377, miR-527-518a, miR-520f-520c) and HER2/neu (miR-520d, miR-181c, miR-302c, miR-376b, miR-30e) receptor status. MiR-342 and miR-520g expression was further analysed in 95 breast tumours. MiR-342 expression was highest in ER and HER2/neu-positive luminal B tumours and lowest in triple-negative tumours. MiR-520g expression was elevated in ER and PR-negative tumours.
This study demonstrates that ANN analysis reliably identifies biologically relevant miRNAs associated with specific breast cancer phenotypes. The association of specific miRNAs with ER, PR and HER2/neu status indicates a role for these miRNAs in disease classification of breast cancer. Decreased expression of miR-342 in the therapeutically challenging triple-negative breast tumours, increased miR-342 expression in the luminal B tumours, and downregulated miR-520g in ER and PR-positive tumours indicates that not only is dysregulated miRNA expression a marker for poorer prognosis breast cancer, but that it could also present an attractive target for therapeutic intervention.

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    • "Ectopic expression of miR-22E mimics inhibited both 180-and 185-kDa HER-3 at about the same rate, whereas miR-22 reduced the 180-kDa HER-3 first and then the 185-kDa protein at a slower rate. Addition of miR-342 (a miRNA targeting at HER-2), used as a negative control, did not affect expression of HER-3 [39] [40]. (b) Addition of ectopic miR-22 inhibitor (lentimiRa-Off-hsa-miR-22) increased both 180-and 185-kDa HER-3 proteins in H23 and H1437 cells as determined by immunoblotting analysis, confirming our previous results that miR-22 reduced HER-3 protein expressions, and the miR-22 inhibitor reversed the suppressive effect by inhibiting the function of miR-22. "
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    • "miR-206 repressed tumor cell migration through direct targeting of the actin-binding protein Coronin 1C (CORO1C) in TNBC [44]. miR-342 expression was shown to be highest in ER and HER2/neu-positive luminal B tumors and lowest in TNBCs, which could present an attractive target for therapeutic intervention [45]. In addition, the let-7 miRNA family is known to act as tumor suppressors in breast cancer and several let-7 miRNAs may induce tamoxifen sensitivity by downregulation of estrogen receptor α signaling in TNBC cell lines [46]. "
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    • "Further, miRNA expression is tissue specific and it has been demonstrated that miRNA expression profiling is more robust in classification of tumours of different origin (Lu et al, 2005). Specifically, in breast cancer, a number of studies defined miRNA expression profiles associated with sporadic breast tumours (Iorio et al, 2005; Volinia et al, 2006, 2012), specific breast cancer subtypes (Blenkiron et al, 2007; Fassan et al, 2009) and tumour biological features such as hormone receptor and HER2 status, metastasis, progression or proliferation (Mattie et al, 2006; Tavazoie et al, 2008; Lowery et al, 2009). There has been longstanding expectation that evolution in molecular profiling may result in pathological classification that more directly reflects the genetic aetiology of non-BRCA1/2 tumours. "
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