Estrogen receptor‐positive breast cancer: a multidisciplinary challenge

Abstract

Estrogen receptor (ER)-positive breast cancer research is an ideal example of how systems biology can be applied to better understand a specific clinical issue. By integrating vast data sets from tumor-derived expression arrays, genome-wide transcription factor/chromatin interactions, proteomics and computational analyses, we may better understand the concept of breast cancer development, heterogeneity, and its treatment. Resistance to endocrine treatment, such as anti-estrogens, often occurs and systems biology may prove to be a valuable asset in tailoring treatment for each patient. In such a multidisciplinary setup, it is essential to try and connect these massive data streams with the known pathological background and cell biology. In this review, we describe the current status of such studies and the challenges that are to be met in order to fully understand the concept of anti-estrogen resistance from a holistic perspective.

A bi-faceted role of estrogen receptor β in breast cancer

“…As outlined in previous reviews (McKenna et al 1999, Lonard et al 2007, Zwart et al 2011, Kumar & McEwan 2012, the resulting effect on gene transcription is a dynamic process, involving multiple protein complexes, which contain chromatin-modifying molecules such as histone deacetylases, protein degradation units involving proteasome and ubiquitin ligase, as well as splicing regulatory units. Nonclassical mechanisms of action have also been described for steroid receptors: these include activation by EGF signaling through ligandindependent phosphorylations of the receptor; tethering of the receptor with other transcription factors, such as Sp1 and AP1 (Hall et al 2001 ; Fig.…”

“…The practical consequences of the concept of inhibiting the mitogenic action of estrogen on breast cancer cells have been the successful establishment of the endocrine therapies for treating breast cancer (Trialists' 1992(Trialists' , 1998 as well as providing options for preventing breast cancer (Fisher et al 2005). While the concept itself is relatively simple, our understanding of the exact molecular mechanisms by which estrogen is involved in these processes continues to evolve and is more complex and multifaceted than originally thought (Zwart et al 2011). In particular, one critical discovery has been the identification of a second estrogen receptor (ER), called ERb (Kuiper et al 1996), in contrast to the classical ERa, which can also mediate estrogen action in target cells.…”

Molecular Insights of Pathways Resulting from Two Common PIK3CA Mutations in Breast Cancer

“…In addition to E2, multiple cofactors and posttranslational modifications control ERa activity (4,5). These include pioneer factors such as FOXA1, GATA3, and AP2g that guide ERa binding to the genome, transcriptional coregulators that influence transcriptional output from ERa, and ERa phosphorylation that influences transcriptional activity, stability, and subcellular distribution (4).…”

Complex Formation and Function of Estrogen Receptor α in Transcription Requires RIP140

“…When activated by estrogen, ERa drives the expression of a large number of target genes, leading to breast tumor cell proliferation. Ligand binding results in receptor dimerization, chromatin association, and the recruitment of a large set of coregulators required for transcription of target genes (19). For ERa to associate with the chromatin, it requires the action of so-called "pioneer factors" to enable chromatin accessibility.…”