The role of thiol-dependent antioxidant enzymes in estrogen receptor-expressing breast cancer

Breast cancer is the most common malignant neoplasm in women. Seventy percent of human breast cancers have the estrogen receptor, which is an extremely attractive target for endocrine therapies. However, a significant percentage of breast cancers treated this way become refractory to this therapy, which is associated with a significant worsening of the prognosis. This often occurs in the mechanism of switching the dependence of tumor growth from estrogen dependent on estrogen in the direction dependent on pathways activated by growth factors, their receptors (GFR) or GFR signaling oncogenic proteins. One of the factors responsible for this phenomenon seems to be the conditions of oxidative stress in neoplastic cells. It is the subject of intense research. Our group, coordinating the work of several centers abroad, recently found that one of the main chains of enzymes (dependent on thiol groups) counteracting oxidative stress protects the estrogen receptor against the effects of this stress. It has also been found in the clinical material from a total of over 1,200 patients that the increased expression in the tumor of the main enzyme of this chain, peroxyredoxin 1 (PRDX1), is a favorable prognostic factor. Based on our preliminary studies and the available results of other research groups, we have created a systemic model in which the enzyme chain PRDX1 / 2thyoredoxin (TXN) plays an important role in maintaining the estrogen / ER pathway dependent type of breast cancer growth. This hypothesis is the basis for setting three research goals to be carried out in vitro in this project. The fourth objective concerns in vivo research, complementing the holistic approach to the studied phenomenon. The four main goals of the current project are: Goal 1: To investigate the molecular mechanisms of ER protein suppression induced by a defect in the function of the thiol-dependent antioxidant enzyme chain. Objective 2: To investigate the role of thiol-dependent antioxidant enzymes in switching signaling in breast cancer between hormone-dependent and oncogen-dependent breast cancer using -omics techniques. Objective 3: To evaluate the regulation of PRDX1 / 2 enzymatic activity in breast cancer. Aim 4. To study the influence of PRDX1 dysfunction on the progression of breast cancer in the in vivo xenotransplantation model.