Cell cycle regulatory proteins and miRNAs in premalignant lesions and breast cancer

Abstract: Early diagnosis and reliable prognosis and treatment prediction of breast cancer will ultimately lead to a decreased mortality rate. This can be achieved by identification of prognostic and treatment predictive biomarkers, and by understanding the mechanisms behind early changes in the breast. The cell cycle is a closely controlled process, involving multiple components with regulation on several levels. Loss of adequate cell proliferation control and cell cycle regulation is one of the main characteristic of cancer. In this thesis we have found that low level of the cell cycle regulatory protein p27 was associated with impaired response to tamoxifen in premenopausal breast cancer patients, but not with prognosis. We have also observed that the expression of the microRNA (miRNA) miR-92a could provide independent prognostic information in breast cancer patients, and loss of miR-92a was associated with more severe breast cancer traits. The earliest histologically identifiable breast lesion with an increased risk for developing breast cancer is called columnar cell hyperplasia (CCH). We have identified miRNA expression changes in CCH compared to normal mammary gland tissue in both epithelial cells and in the surrounding stroma. In addition we have linked epithelial expression of miR-27a, miR-92a andlet-7c to negative cell proliferation regulation, and stromal miR-I32 expression to alteration of genes associated with extra cellular matrix and actin-motility pathways in fibroblasts, and metabolic genes and pathways in co-cultured CCH epithelial cells. Finally, cyclin Dl associated miR-483-5p affected cell migration in opposite directions depending on estrogen receptor status, highlighting the importance of subdivision of breast cancers in order to correctly understand the biology and subsequently for correct treatment of breast cancer subgroups. In summary, these studies identified two potential biomarkers; one for predicting tamoxifen sensitivity, and one with prognostic value. We also revealed changes in miRNA expression in early premalignant breast lesions involved in cell proliferation, and opposing roles in cell migration for a cell cycle-related miRNA in breast cancer subgroup models.