Bioinformatics prediction of rs4919510 within miR-608 and schematic representation of potential pathological mechanism of rs4919510 in HER2-positive breast cancer development.

<p>A, the predicted secondary structure of human miR-608 stem-loop sequence (100 bp) by RNAfold, with either the C- allele or G-allele. For ancestral form with C-allele, the optimal secondary structure with a minimum free energy (MFE) of −32.20 kcal/mol. The frequency of the MFE structure in the ensemble is 0.53%, and the ensemble diversity is 13.52. For the variant form, the optimal secondary structure with the same MFE of −32.20 kcal/mol. The frequency of the MFE structure is 0.33%, and the ensemble diversity is 14.09. The structure plot shows that variant G-allele strongly interfere with loop forming. B, HSF1 is a predicted target of miR-608 and rs4919510:C>G is just located at the complementary sequence. Asterisk indicates the polymorphic site. The plot of predicted duplex formation is from MicroCosm Targets website. C, Predicted secondary structure of duplex formation between miR-608 and 3′UTR of HSF1 by RNAhybrid. rs4919510:C>G changes the MFE, with ancestral form of −35.9 kcal/mol and variant form of −31.5 kcal/mol. D, schematic representation of speculated pathological mechanism of rs4919510 in HER2-positive breast cancer development. In this model, miR-608 harbouring the rs4919510-C allele (ancestral form) is set as the baseline condition. The C-to-G substitution might weaken the suppression of HSF1 mRNA by miR-608, leading to relatively high expression of HSF1 protein and, in turn, up-regulating HSPs and facilitating HER2-expressing normal or precancerous breast cells to transform cancer cells. HSPs also promote tumor cell proliferation. After cancer evolutionary selection, HER2-overexpressed or HER2-amplified tumor is formed since HER2+ cells are easy to survive under HSF1/HSPs stimulating. Moreover, overexpression of HER2 would activate HSF1 and promote HSF1 protein synthesis, further upregulating HSPs and facilitating tumorigenesis and development of HER2+ breast cancer.