PI3K/AKT and MAPK1 molecular changes preceding matrix metallopeptidases overexpression during tamoxifen-resistance development are correlated to poor prognosis in breast cancer patients.

Abstract

Metastasis and drug resistance remain a persistent key clinical obstacle to the success of breast cancer treatments. Recent years have seen an increased focus on understanding the factors that influence metastasis and drug resistance. In this study, the changes in MMPs gene expression were investigated together with their regulatory pathways-PI3K, MAPK and NFKβ pathways-during the process of developing tamoxifen resistance in MCF7 cell line. Gene correlation maps and Kaplan-Meier survival plots among all breast cancer patients and patients treated with tamoxifen were evaluated. MMPs gene expression was found to be up regulated in MCF7 cell line treated with tamoxifen during the development of tamoxifen resistance using two approaches. Up-regulation of gene expression of AKT1 and MAPK1 started in cells treated with 10μM tamoxifen that was followed with up-regulation of other genes in these pathways and MMPs in cells treated with 35μM tamoxifen. MMPs and genes from PI3K, MAPK and NFKβ pathways showed highly significant increase of expression at 50μM or when cells were treated sequentially six times with 35μM. Furthermore, increased genes expression was associated with aggressive pattern, clear morphological changes, higher growth rate, increased migration and adhesion potential and tamoxifen insensitivity. Breast cancer distant metastasis-free survival, and survival among tamoxifen treated patients had high expression levels of MAPK1, AKT1, TIMP2, MMP1, and MMP9 showed poor prognosis. Early changes of MAPK1, AKT1 gene expression upon tamoxifen treatment could possibly be used as an early marker of resistance and future poor prognosis.