Browsing by Subject "Breast cancer"

Breast cancer is the most prevalent cancer in women worldwide and in 2020 it was the fifth deadliest. In Finland 2019 more than 5000 breast cancer cases were diagnosed, 94% in women and 6% in men. Until now, the high-risk breast cancer susceptibility genes have been identified including BRCA1, BRCA2 and TP53 as well as many of the moderate risk genes. Still, together all the identified genes explain only approximately half of the familial breast cancer cases. Furthermore, all the known breast cancer susceptibility genes are linked to the DNA repair mechanism. Serpina3 stands out as a non-DNA repair gene but as a gene that encodes a protease inhibitor which belongs to the serpin superfamily. Serpina3 has been associated with various diseases before and especially changes in its expression levels are linked to the tumor prognosis in many cancers including breast cancer. However, a previous study proposed that Serpina3 c.918-1G>C is a susceptibility variant for breast cancer in the Northern Finland population. This thesis a case-control study to investigate whether Serpina3 c.918-1G>C variant is associated with breast cancer in the Southern Finland population. In addition, the tumor histology and cellular markers of Serpina3 c.918-1G>C carriers were examined. This study utilized DNA collected from breast cancer patients as well as DNA from blood donors and healthy biobank controls. Breast cancer patients included both familial and unselected cases. The prevalence of Serpina3 c.918- 1G<C variant was studied by genotyping the cases and controls. Genotyping was done by TaqMan real-time PCR and carriers were further confirmed by Sanger sequencing. Moreover, statistical tests were used in the data analyses. The studied Serpina3 c.918-1G>C variant was not found to be significantly (p>0.05) enriched in the breast cancer cases. The variant was found in 0.23 % of familial and 0.36 % of unselected cases, altogether in 0.28 % of all studied breast cancer cases, the frequency in controls was 0.27 %. The tumor histology was found to be ductal in 73 % of the Serpina3 c.918- 1G>C variant carriers and only 9 % had lobular tumor. In other words, the tumor histology followed the usual distribution. All the carriers had a HER2 negative tumor and all except one case were both ER and PR positive. About half of the carriers expressed the cellular proliferation marker Ki67. As a conclusion, the results from this study do not suggest Serpina3 c.918-1G>C as a breast cancer risk variant at least in the Southern Finland population.

Triple-negative breast cancer (TNBC) accounts for 10-15% of all breast cancer cases and has the worst clinical outcome. Characterizing features of TNBC are high recurrence and mortality rates, and the absence of three commonly targetable breast cancer biomarkers estrogen receptor, progesterone receptor, and HER2, limiting the number of targetable therapy options. Cytotoxic CD8 positive T cells play a crucial role in the anticancer immune response and act as a major component of successful cancer immunotherapies. However, cancer cells can evade T cell-mediated killing by overexpressing programmed death-ligand 1 (PD-L1) resulting in T cell exhaustion and limited immune response via the interaction with programmed death protein 1 (PD-1). Systemic anti-PD-L1/PD-1 therapies aim to prevent this immunosuppressive mechanism, but they are burdened with potentially life-threatening autoimmunity-type adverse effects. Therefore, cancer cell-specific targets to downregulate PD-L1 could offer efficacious and less harmful ways to overcome PD_L1/PD-1 mediated immunosuppression. Serine protease hepsin is commonly overexpressed in many solid tumors where it is responsible for the activation of HGF/MET signaling pathway as well as degradation of desmosomes and hemidesmosomes leading to the loss of epithelial integrity, invasion, and metastasis. Earlier studies have linked hyperactive HGF/MET pathway to the upregulation of immune checkpoint molecule PD-L1. In this thesis, I show how pharmacological inhibition of hepsin leads to decreased MET activity and downregulation of PD-L1 in a panel of TNBC cell lines. My results demonstrate the potential of hepsin-mediated regulation of PD-L1 in tumor immunosuppression, and hint at the potential of hepsin as a therapeutic avenue towards safe and efficacious immunotherapy in the future. These results are part of a larger study addressing the role of hepsin as a regulator of PD-L1 breast cancer.