The objective of this study was to investigate the expression and function of GRHL2 in different breast cancer subtypes. In Chapter 2, we focused on the expression of GRHL2 in human breast cancer... Show moreThe objective of this study was to investigate the expression and function of GRHL2 in different breast cancer subtypes. In Chapter 2, we focused on the expression of GRHL2 in human breast cancer and the distinct effects of GRHL2 knockout on aspects of growth versus migration in basal A and luminal-like subtypes. In Chapter 3, ChIP-seq was used to explore the genomic landscape of GRHL2 binding sites in basal A and luminal-like subtypes of breast cancer and this data was used to predict shared and distinct GRHL2 target genes. In Chapter 4, based on a conditional GRHL2 knockout system, we determined the dynamic changes in genome-wide DNA transcription triggered by loss of GRHL2 in luminal-like breast cancer cells and used the data to predict affected pathways. In Chapter 5, ChIP-seq and BrU-seq data were integrated to identify genes whose transcription is controlled by GRHL2 and establish gene expression networks regulated by GRHL2 in luminal-like breast cancer. Show less
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
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
