Mechanisms of endocrine resistance in breast cancer

Abstract

The estrogen receptor (ER) pathway plays a pivotal role in breast cancer development and progression. Endocrine therapy to block the ER pathway is highly effective, but its usefulness is limited by common intrinsic and acquired resistance. Multiple mechanisms responsible for endocrine resistance have been proposed and include deregulation of various components of the ER pathway itself, alterations in cell cycle and cell survival signaling molecules, and the activation of escape pathways that can provide tumors with alternative proliferative and survival stimuli. Among these, increased expression or signaling of growth factor receptor pathways, especially the EGFR/HER2 pathway, has been associated with both experimental and clinical endocrine therapy resistance. New treatment combinations targeting both ER and growth factor receptor signaling to block the crosstalk between these pathways and eliminate escape routes have been proven highly effective in preclinical models. Results of recent clinical studies, while partly supporting this approach, also highlight the need to better identify a priori the patients whose tumors are most likely to benefit from these specific cotargeting strategies.

Figure 1. Mechanisms of Estrogen Receptor (ER) Action in Breast Cancer

Estrogen (E)-bound ER, acting as a transcription factor in the nucleus (nuclear/genomic activity), binds to DNA sequences in promoter regions of target genes either directly (at estrogen receptor elements; EREs) or indirectly via protein-protein interaction with other transcription factors at their cognate DNA responsive sites (e.g., members of the AP-1 or the SP-1 transcription complexes at AP-1 or SP-1 sites). Upon estrogen binding, ER generally recruits coactivator complexes (CoA) to induce or modulate gene transcription including genes coding growth factors (GFs) and receptor tyrosine kinases (RTKs) (A). A small subset of the cellular pool of ER localized outside the nucleus and/or at the cell membrane associates in response to estrogen with growth factor RTKs (e.g., EGFR, HER2, and IGF1-R) (B) and with additional signaling and coactivator molecules (e.g. the Src kinase) (C). This interaction, similar to GF activation of these pathways, activates multiple downstream kinase pathways (e.g., Src, PI3K/AKT, and Ras/p42/44 MAPK) which in turn phosphorylate various transcription factors (TFs) and coregulators, including components of the ER pathway that enhance gene expression on EREs and other response elements (RE). The nonnuclear/nongenomic activity, which can also be activated by tamoxifen, is enhanced in the presence of overexpression and hyperactivation of RTKs and can contribute to endocrine therapy resistance. Overall, the nuclear/genomic and nonnuclear/nogenomic ER activities work in concert to provide breast tumor cells with proliferation, survival and invasion stimuli. Signaling from the microenvironment activates stress related pathways and members of the integrin family. These pathways then trigger downstream kinase pathways (e.g., FAK, JNK and p38 MAPK) that can further modulate components of the transcriptional machinery, including ER (D). Alterations in each of these transcriptional and signaling elements can mediate resistance to endocrine therapy either by modulating ER activity or, by acting as escape pathways to provide alternative proliferation and survival stimuli.