The Polyamine Dependence of Cell Cycle Progression-Application in Breast Cancer Treatment

Abstract: In the normal functioning organism, there is a balance between cell proliferation, cell differentiation, and cell death. An imbalance in these processes results in different diseases. This thesis concerns the imbalance where there is too little cell death and cell differentiation with increased cell proliferation. The result is uncontrolled cell proliferation resulting in the development of cancer. Polyamines are essential for normal cell cycle proliferation and polyamine levels are often elevated in cancer cells. The general aim of my thesis was to achieve a better understanding of the role of the polyamines in cell cycle progression and how to apply this to manipulate the breast cancer cell cycle. In one model system we investigated cell cycle progression in Chinese hamster ovary cells expressing different types of an enzyme involved in polyamine biosynthesis resulting in different polyamine pool levels. In the second model system we depleted the polyamines in four breast cancer cell lines with different genetic profiles to resemble the reality of breast cancer disease, and in one normal-like breast epithelial cell line. The substances we used to deplete the polyamines were: alpha-difluoromethylornithine, 4-amidinoindan-1-one 2'-amidinohydrazone, and, N1, N11-diethylnorspermine. Cell cycle kinetics was affected in both model systems by manipulation of the polyamine pools. The different cell lines responded differently to the same kind of treatment and different signaling pathways were induced. This resulted in different responses in cell cycle kinetics such as S phase prolongation and G1/S block. The cell cycle kinetic effects were correlated to changes in the levels of cell cycle regulatory proteins. The responses in the human cell lines can be reflected in their different genetic makeup. Altogether these data show the importance of finding biomarkers for the efficient use of compounds that affect the polyamine pools in the treatment of breast cancer. The result show that DENSPM treatment and almost certainly other spermine analogues may be effective in certain types of familial breast cancer sub groups while ineffective in other types of breast cancer.