Cell cycle perspectives on breast cancer cell behaviour

Detta är en avhandling från Lund University, Faculty of Medicine

Sammanfattning: Uncontrolled proliferation and the capacity to infiltrate surrounding tissues are two important characteristics of aggressive tumour cells. Previous observations in both colorectal cancer and basal cell carcinoma indicated that infiltrative tumour cell behaviour might be counteracted by a high proliferative activity, suggesting a coordination of these two activities at the cellular level. Here we studied the potential relation between proliferative activity and migratory behaviour in breast cancer, by focusing on the cell cycle regulatory proteins cyclin E and cyclin D1. By expressing cyclin E in a breast cancer cell line we obtained experimental results indicating that increased proliferative activity obstructed migratory and invasive capacity. When validating these results in a large set of primary breast cancers, we observed that increasing cyclin E levels correlated with a less infiltrative tumour growth appearance – a finding in line with our experimental results. Several studies have proposed that cyclin E is strongly associated with poorer disease outcome in breast cancer. Therefore, we continued to investigate the potential prognostic relevance of the inverse relation between cyclin E and infiltrative tumour growth. We revealed a distinct subgroup of less infiltrative, cyclin E high breast cancers with a relatively favourable prognosis. This subgroup was an important exception compared to the majority of tumours where cyclin E indeed correlated to a poorer outcome. We also tried to delineate in detail how the migratory capacities of tumour cells related to cell cycle activities. Synchronised G0/early G1 cells displayed an increased migratory potential compared to both late G1/S-phase cells as well as unsynchronised, actively cycling cells. Further, silencing of cyclin D1 in two cell lines indicated a novel CDK- and cell cycle independent function of cyclin D1 in restraining migratory capacity. This novel role of cyclin D1 seemed to influence the behaviour of ER positive breast tumours, where cyclin D1 high tumours were in general of smaller size and, further, exhibited a somewhat less infiltrative growth pattern. In addition, increased cyclin D1 levels correlated to a more favourable prognosis.