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)