Public examination of a doctoral dissertation in the field of toxicology
Doctoral candidate: FM Marjo Huovinen
Time and venue: 2.12.2011, Canthia L3, Kuopion kampus
Language of the public examination: Finnish
Language of the dissertation: English
Breast cancer is the most common cancer in women and there are indications that tobacco smoke may increase the risk of this disease. This proposal is supported by epidemiological data and studies in experimental animals. Tobacco smoke contains polycyclic aromatic hydrocarbons (PAHs) which are formed during incomplete combustion of organic material. Benzo(a)pyrene (BP) belongs to the PAHs and it has been used as a model compound of PAHs.
The aim of this study was to clarify the BP-induced p53-mediated responses protecting cells from the carcinogenic effects of BP in human breast cancer cell lines. First, the TP53 gene from five different cell lines was sequenced for the presence of mutations, and the ability of the cells to metabolize BP was studied. In order to be active, p53 protein has to be post-translationally modified e.g. phosphorylated or acetylated, in certain amino acids. p53 protein induction and phosphorylation were studied after BP treatment and the characteristics of BP-induced cell death were also evaluated. The results in five different breast cancer cell lines were compared to determine whether the responses of BP were breast tissue specific or cell line specific.
Four of the five studied breast cancer cell lines formed benzo(a)pyrene-diol-epoxide-DNA (BPDE-DNA) adducts, indicative of functional metabolism of BP. Two of the cell lines contained a wild type TP53 gene (wtTP53) which is a prerequisite if one wishes to study the normal p53 pathway. When different types of p53 phosphorylations were examined, it was found that phosphorylation at serine 392 was the first stabilizing modification after BP-treatment in the breast cancer cell line containing wtTP53. In the other cell lines containing mutated TP53, there was no clear evidence for phosphorylation at serine 392. However, the presence of other phosphorylations revealed that mutated p53 can be phosphorylated. BP-induced cell death was mediated, at least partly, through p53-dependent apoptosis at least in MCF-7 cells and possibly also in ZR-75-1 cells. These findings are supported by the changes in several apoptotic proteins after BP-treatment.
In conclusion, this work supports data from the literature for the presence of BPDE-DNA adducts in breast tissue in vivo and for the formation of mammary tumors in experimental animals after BP-treatment. The hypothesis that exposure to PAHs is one of the risk factors for breast cancer is supported by the findings in the human breast cancer cell lines: 1) formation of BPDE-DNA adducts after BP-treatment, 2) p53 protein induction and phosphorylation which are evidence of p53 activation, and 3) induction of apoptotic cell death which is believed to be an attempt to protect the tissue from the harmful effects of BP.
The doctoral dissertation of Master Science Marjo Huovinen, entitled Effects of benzo(a)pyrene in human breast cancer cell lines related to chemical carcinogenesis will be examined at the Faculty of Health Sciences. The opponent in the public examination will be Docent Kaisa Unkila of Orion Pharma, Turku, and the custos will be Professor Kirsi Vähäkangas of the University of Eastern Finland.
Photo available for download at http://www.uef.fi/vaitoskuvat
For further information, please contact: Marjo Huovinen, tel. 040 3552419, marjo.huovinen(at)uef.fi
Publishing year: 2011Back to this years article listing