In this thesis we reflect on the effects differential DNA binding of the estrogen receptor α (ERα) can have on the behavior of breast cancer and which factors can contribute to this. ERα is a... Show moreIn this thesis we reflect on the effects differential DNA binding of the estrogen receptor α (ERα) can have on the behavior of breast cancer and which factors can contribute to this. ERα is a transcription factor than can drive tumor cell proliferation and approximately 70% off all breast tumors is thought to be dependent on the activity of this hormone-mediated transcription factor. After stimulation of ERα a wild variety of co-factors are recruited, leading to the assembly of a transcriptional complex. Although there are multiple ways of targeting the action of ERα and thereby inhibiting tumor growth, still a significant proportion of patients develop a recurrence. Cross-resistance between the different endocrine therapy options can occur, but a proportion of patients that relapse on one type of therapy can still benefit from a different treatment modality, illustrating the existence of multiple resistance mechanisms which can be treatment selective. A better understanding of ERα-biology and the development of endocrine therapy resistance, can lead the way to the discovery of novel biomarkers and potential drug targets, that can further increase patient survival. Show less
Although the survival of breast cancer has improved the past decades, there is still major over- and undertreatment for the majority of patients. The aim of this research was to identity the most... Show moreAlthough the survival of breast cancer has improved the past decades, there is still major over- and undertreatment for the majority of patients. The aim of this research was to identity the most optimal adjuvant endocrine therapy, with regard to the optimal duration of therapy and the selection of subgroups who require selected therapy. Show less
Upon activation by estrogen, the Estrogen Receptor binds the chromatin and influences gene transcription. This ultimately leads to cell proliferation. About 75% of breast cancer patients... Show moreUpon activation by estrogen, the Estrogen Receptor binds the chromatin and influences gene transcription. This ultimately leads to cell proliferation. About 75% of breast cancer patients express this hormonal receptor. These patients are often treated with tamoxifen, which competitively inhibits the proliferative effects of estrogen in breast cancer cells. While tamoxifen inhibits the tumor growth of breast cancer, its effects in other Estrogen Receptor-positive tissues vary, as reviewed in chapter 1. Its most adverse side-effect is that it increases the risk for endometrial cancer. Chapters 2 and 3 describe the effects of tamoxifen on the DNA binding sites of the Estrogen Receptor in tamoxifen-associated endometrial cancer, and the similarities of these binding sites with those found in breast cancer. Unfortunately, there are Estrogen Receptor-positive breast cancer patients who do not respond to hormonal treatment. Chapter 4 reveals a key-role for activating transcription factor 2 on tamoxifen’s inhibitory response on cell proliferation. Chapter 5 discusses components of the Estrogen Receptor pathway and highlights their potential as biomarkers in hormonal response therapy. Finally, chapter 6 provides new questions invoked by this thesis, and discusses the importance of unraveling the Estrogen Receptor pathway in multiple tissues in order to develop tailor-made treatments. Show less
