Transcriptional Control of Oncogenic Processes in Breast Cancer Cells by the Estrogen Receptors
Jonsson, Philip 1985-
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The estrogen receptors are fundamental factors in human biology. As transcriptional factors regulating gene programs controlling many processes in the body, they are key in both development and disease. Also, as nuclear receptors they can be activated or blocked by specific ligands, making them excellent targets for therapeutics. This dissertation focuses on the study of the estrogen receptors, both the alpha and beta isoforms (ERα and ERβ, respectively), and how they regulate gene transcription in human breast cancer. The proliferative role of ERα in breast cancer remains poorly understood. Here we show that the ion channel KCNK5 is a direct transcriptional target of ERα in breast cancer cell lines MCF7 and T47D. Also, we show that this is reflected by changes in the ion channel’s protein. Furthermore, silencing of the ion channels expression reduces cellular proliferation, as well as the estrogen-induction of proliferation. This uncovers ion channels as potential factors in the proliferation of breast cancer, as well as potential targets in novel treatment approaches. ERα’s role as a transcription factor has predominantly been studied in regards to its regulation of protein-coding genes. Herein, we show that ERα also regulates non-coding RNAs, such as long non-coding RNAs and pseudogenes. We also potentially uncover novel protein-coding targets, by the use of novel RNA- sequencing technology, and the use of microarrays. The other estrogen receptor, ERβ, is less characterized, but it is considered to be anti-proliferative in breast cancer and its activation suggested as a potential future therapy. However, discordant results of expression in breast tumors, correlation to prognosis, and tumor-suppressive function in cell lines have made this a debated field. We explore its role in breast cancer cells further and show that, in certain contexts, ERβ is not able to suppress breast cancer cell proliferation, nor, as often suggested, counteract ERα-mediated signaling. This warrants further studies into whether its activation in breast cancer is a desirable treatment.