The interaction between ER and NFκB in resistance to endocrine therapy

Breast Cancer Research, Aug 2012

Endocrine therapy is a commonly used treatment for estrogen receptor (ER)-positive breast cancer. Although endocrine therapy has a favorable outcome in many patients, development of resistance is common. Recent studies have shown that NFκB, a transcription factor regulating a wide variety of cellular processes, might play a role in the development of endocrine resistance. The precise interaction between ER and NFκB and how this contributes to the attenuated responsiveness of ER-positive breast cancer cells to hormonal treatment remains unclear. This review provides an overview of the mechanisms of action for both transcription factors and focuses on the current knowledge explaining how ER and NFκB affect each other's activity and how this cross-talk might contribute to the development of an endocrine resistance phenotype in breast cancer cells.

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The interaction between ER and NFκB in resistance to endocrine therapy

Breast Cancer Research The interaction between ER and NFкB in resistance to endocrine therapy Leen Sas 0 2 3 Filip Lardon 2 Peter B Vermeulen 0 3 Jan Hauspy 0 3 Peter Van Dam 0 3 Patrick Pauwels 2 Luc Y Dirix 0 3 Steven J Van Laere 0 1 3 0 Translational Cancer Research Unit, Oncology Center, GZA Hospitals St-Augustinus , 2610 Antwerp , Belgium 1 Division of Gyneacological Oncology, Department of Oncology, University Hospital Leuven, Catholic University Leuven , Herestraat 49, 3000 Leuven , Belgium 2 Department of Oncology, University of Antwerp, Universiteitsplein 1 , 2610 Antwerp , Belgium 3 Translational Cancer Research Unit, Oncology Center, GZA hospitals St- Augustinus , Oosterveldlaan 24, 2610 Antwerp , Belgium Endocrine therapy is a commonly used treatment for estrogen receptor (ER)-positive breast cancer. Although endocrine therapy has a favorable outcome in many patients, development of resistance is common. Recent studies have shown that NFкB, a transcription factor regulating a wide variety of cellular processes, might play a role in the development of endocrine resistance. The precise interaction between ER and NFкB and how this contributes to the attenuated responsiveness of ER-positive breast cancer cells to hormonal treatment remains unclear. This review provides an overview of the mechanisms of action for both transcription factors and focuses on the current knowledge explaining how ER and NFкB affect each other's activity and how this cross-talk might contribute to the development of an endocrine resistance phenotype in breast cancer cells. Introduction Breast cancer is one of the leading causes of cancerrelated death in women. Gene expression profiling studies have shown that breast cancer is a heterogeneous disease consisting of at least five subtypes [ 1,2 ]. Independent studies have shown that the estrogen receptor (ER) signaling pathway, tumor cell proliferation and epidermal growth factor receptor/ErbB2 amplification are the main drivers for breast cancer heterogeneity [ 3,4 ]. Overall, the two major subgroups of breast cancer that can be distinguished are stratified according to their ER status. The ER-positive breast tumors are referred to as luminal tumors, indicating that these tumors supposedly originate in the luminal cell layer of the breast gland. The group of luminal tumors can be subdivided into luminal A and luminal B tumors, based on differences in expression for a series of luminal genes (attenuated in the luminal B tumors) and proliferation genes (overexpressed in the luminal B tumors). Evidence suggests that the strongly proliferating luminal B-type tumor cells are less responsive to endocrine therapy, which is the mainstay of treatment for patients with ER-positive breast cancer. Fan and colleagues have shown that approximately 90% of the patients with luminal B-type tumors exhibit a high recurrence score, which indicates that these patients bear tamoxifen-resistant tumors [ 5,6 ]. Keeping in mind the already established relationship between endocrine therapy resistance and activated growth factor signaling pathways (for example, mitogen-activated protein kinase or phosphatidylinositol-3 kinase), which contribute to cell proliferation, this observation is not unexpected. Activated growth factor signaling is believed either to downregulate ER protein expression or to enhance ER activity in a ligand-independent manner and, as such, provides a means for tumor cells to escape from the inhibitory actions of the anti-estrogens [ 7-10 ]. On the other hand, Fan and colleagues also demonstrated that up to 30% of the patients with luminal A-type tumors exhibit high recurrence scores [ 6 ]. Given the fact that luminal A-type breast tumors are generally slowly proliferating tumors, these data suggest that other factors contribute to the attenuated responsiveness of ER-positive breast cancer cells to endocrine therapy and therefore these factors may be potential targets for modulating endocrine responsiveness. Recent data have demonstrated that the activity of NFкB, a transcription factor promoting expression of genes related to several oncogenic processes, is linked with ER signaling in breast cancer cells, although the exact nature of the interaction remains vague [ 11,12 ]. Several studies have suggested that ER and NFкB may attenuate each other’s activities. Inhibition of ER by antiestrogens might thus release NFкB from ER-driven inhibition, resulting in NFкB-driven tumor progression. Vice versa, NFкB may downregulate ER expression or attenuate its activity, giving rise to ER-negative or ER-irresponsive cell populations that are naturally resistant to endocrine therapy. In contrast, other studies have suggested a synergy between ER and NFкB activity, leading to the transcription of genes involved in aggressive tumor cell behavior, such as multidrug resistance proteins and prosurvival factors. Of note, NFкB can also be stimulated by growth factor signaling path (...truncated)


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Leen Sas, Filip Lardon, Peter B Vermeulen, Jan Hauspy, Peter Van Dam, Patrick Pauwels, Luc Y Dirix, Steven J Van Laere. The interaction between ER and NFκB in resistance to endocrine therapy, Breast Cancer Research, 2012, pp. 212, 14, DOI: 10.1186/bcr3196