Breast and ovarian cancers are the most serious cancers among women. Relatively high mortality at advanced stages of the disease is often associated with the development of resistance to the cytotoxic agents. Chemoresistance usually develops on the base of different adaptive mechanisms that significantly decrease therapy efficiency. Currently TRIP6, ABCC3 and CPS1 enzyme has been identified based on high-capacity expression profile monitoring in tumor cell and tissue profiles as one such candidate playing a role in taxane resistance. The main goal of this thesis was to clarify the role or possible association of the ABCC3, CPS1 and TRIP6 genes with the development of tumor cell resistance to taxanes in models of sensitive and paclitaxel-resistant ovarian cancer cells and in the cohorts of patients with ovarian and breast cancer. The in vitro part compares the efficacy of paclitaxel and taxane derivatives in the sensitive and resistant ovarian cancer cell lines and clarifies the association between the different structure of taxane derivatives and the change in CPS1 expression after their application. The study in patient's cohorts with ovarian cancer reveals a relationship between higher levels of the CPS1 gene and shorter progression-free survival. The achieved results may serve as a base for data...

Mechanical tension is an important regulator of cell proliferation, differentiation, migration and cell death. It is involved in the control of tissue architecture and wound repair and its improper sensing can contribute to cancer. The Hippo tumor suppressor pathway was recently shown to be involved in regulating cell proliferation in response to mechanical tension. The core of the pathway consists of the kinases MST1/2 and LATS1/2, which regulate the target of the pathway, the transcription co-activator YAP/ TAZ (hereafter referred to as YAP). When the Hippo pathway is inactive, YAP remains in the nucleus and promotes cell proliferation and stem cell maintenance. When the Hippo signaling pathway is turned on, MST1/2 phosphorylate and activates LATS1/2. LATS1/2 phosphorylates and inactivates YAP in the cytoplasm which is sequestered and degraded, stopping cell proliferation and promoting differentiation of stem cells. Mechanical forces are transmitted across cells and tissues through the cell-cell junctions and the actin cytoskeleton. However, the factors that connect cell-cell junctions to the Hippo signaling pathway were not clearly known. We identified a LIM domain protein called TRIP6 that functions at the adherens junctions to regulate the Hippo signaling pathway in a tension-dependent manner. TRIP6 responds to mechanical tension at adherens junctions and regulates LATS1/2 activity. Under high mechanical tension, TRIP6 sequesters and inhibits LATS1/2 at adherens junctions to promote YAP activity. Conditions that reduce tension at adherens junctions by inhibition of actin stress fibers or disruption of cell-cell junctions reduce TRIP6-LATS1/2 binding, which activates LATS1/2 to inhibit YAP. Vinculin has been shown to act as part of a mechanosensory complex at adherens junctions. We show that vinculin promotes TRIP6 inhibition of LATS1/2 in response to mechanical tension. Furthermore, we show that TRIP6 competitively inhibits MOB1 (a known LATS1/2 activator) from binding and activating LATS1/2. Together these findings reveal TRIP6 responds to mechanical signals at adherens junctions to regulate the Hippo signaling pathway in mammalian cells.