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Browsing by Subject "tamoxifen resistance"

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  • Patrikainen, Linda (2023)
    Breast cancer is globally the leading cause of death in women. ER positive, HER2 negative breast cancer is the most common subgroup, covering two thirds of all breast cancer cases. The different isoforms of ERα, ERα66 and ERα36 are responsible of genomic and non-genomic ER signaling respectively. Tamoxifen is one of the most used drugs in ERα+ breast cancer. As a SERM tamoxifen blocks the activity of ERα66, but plays as an agonist for ERα36, which is associated with tamoxifen resistance. Tamoxifen resistance concerns more than 25% patients with ERα+ breast cancer but the molecular mechanisms that lead to development of resistant disease remain uncovered. Thus, the aim of this thesis was to reveal how two different ERα isoforms are used and regulated in tamoxifen resistance in two commonly used ERα+ breast cancer cell lines MCF7 and T47D. We studied the effect of hormones to tamoxifen sensitivity and to utilization of ERα isoforms. Additionally, we compared the transcriptomics of resistant and parental cells in both cell lines and tested how inhibition of key regulators affect the sensitivity against tamoxifen. In this thesis we report that MCF7 and T47D cell lines obtain different mechanisms of tamoxifen resistance, and that the development of tamoxifen resistance is a parallel process with the cell identity switch from luminal to basal. The EZH2 is involved in maintaining the luminal progenitor type of mammary cells, whereas c-Myc is highly expressed in the resistant cell lines. Hence, EZH2 and c-Myc are key players in development of tamoxifen resistance and could be considered as therapy targets in ERα+ breast cancers.