As EGFR was found to induce miR-7 expression through a Ras/ ERK/Myc pathway, which promoted cell growth and tumor formation, indicating an indirect feedback loop. The expression of the EGFR has also been negatively associated with the expression of miR-30c, which was, identified as an independent predictor of outcome in advanced breast cancer; high expression of miR-30c was associated with benefit of Tamoxifen. Cross-talk between ER and EGFR and its family of growth factor receptors, especially in its activated phosphorylated form, has also been shown to be strongly associated with Tamoxifen resistance.
We previously conducted a study of mRNA expression in patient samples from the discovery set and found no significant association between EGFR mRNA levels and tumor grade, but a significant association with outcome. Furthermore, using the same patient material, a significant correlation between the level of pEGFR and outcome was also observed on a tissue microarray, but again, no correlation with grade was observed. It is well-known that tumor grade is a predictor of poor outcome. The cause of this lack of consistency between the miRNA and mRNA studies with regards to associations to outcome may reflect the complexity of the biological system with multiple miRNAs per target, and that miRNAs have several targets. Furthermore, the apparent indirect feedback loop between miR-7 and EGFR is affected by several other factors, likely masking the known association with grade to outcome. The miRNAs that exhibited the most variable expression in the individual set and overlapped across the three sets were selected, yielded a set of 31 miRNAs. Since the discussed miRNAs were identified by unsupervised analysis, whether they merely depict the cellular architecture of the tumors or are actually masked markers for the tumors ability to progress despite adjuvant treatment with a target-specific drug remains to be determined.
One fourth of the 31 miRNAs were found to be associated with EMT/MET and stem cell characteristics, and the notion that cancer stem cells play an important role in endocrine resistance has recently been discussed. Further studies into this field are needed. It would also be interesting to conduct in situ hybridization of the identified miRNAs to visualize the cells they are expressed in. Also, functional studies would clarify whether targeting surrounding tissue would induce tumor regression, since it is well-known that the microenvironment and malignant cells interact. Overall, the number of patients in this study provides a strong foundation for the debate on miRNAs and benefit of Tamoxifen in post-menopausal ER+ breast cancer patients. This global analysis, employing the microarray-technique, allows a general estimation of miRNAs potential and is a common XL-184 849217-68-1 hypothesis-generating method. This also implies, however, that the significance of single miRNAs expressed by a subgroup of patients with yet unknown characteristics may be masked when assessing the groups collectedly as only general differences are detected. In conclusion, our data seems to indicate that no single miRNA profile predictive of outcome for tumors from ER+ breast cancer patients receiving adjuvant Tamoxifen mono-therapy can be identified.