Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance

Abstract

Breast cancer evolution and tumor progression are governed by the complex interactions between steroid receptor [estrogen receptor (ER) and progesterone receptor] and growth factor receptor signaling. In recent years, the field of cancer therapy has witnessed the emergence of multiple strategies targeting these specific cancer pathways and key molecules (ER and growth factor receptors) to arrest tumor growth and achieve tumor eradication; treatment success, however, has varied and both de novo (up front) and acquired resistance have proven a challenge. Recent studies of ER biology have revealed new insights into ER action in breast cancer and have highlighted the role of an intimate crosstalk between the ER and HER family signaling pathways as a fundamental contributor to the development of resistance to endocrine therapies against the ER pathway. The aim of this review article is to summarize the current knowledge on mechanisms of resistance of breast cancer cells to endocrine therapies due to the crosstalk between the ER and the HER growth factor receptor signaling pathways and to explore new available therapeutic strategies that could prolong duration of response and circumvent endocrine resistant tumor growth.

Figure 1

Nuclear genomic ER activity. ER, in its classical action (A), directly binds to DNA sequences called estrogen response elements (EREs) residing in the promoter region of target genes, and by recruiting coregulatory proteins regulates gene transcription. Estrogen (E2)-bound ER generally recruits coactivator (CoA) complexes to induce gene transcription, whereas estrogen antagonists such as tamoxifen (Tam) mostly lead to ER association with corepressor (CoR) complexes, thereby turning off gene transcription. In its nonclassical action (B), ER regulates gene transcription via protein-protein interaction (e.g., with Fos/Jun family members) that tether ER to DNA sites responsive to other transcription factors such as AP-1. Together, all of these nuclear ER genomic activities also are called nuclear-initiated steroid signaling (NISS).

Figure 2

Integration of genomic and nongenomic/rapid ER signaling and its crosstalk with growth factor receptor and cell kinase pathways in endocrine resistance: a working model. The ligand estrogen (E2) induces genomic ER activity in the nucleus (N), which results in increased gene transcription, including important genes in the growth factor receptor pathways. The SERM tamoxifen (Tam) antagonizes this activity. However, both estrogen and tamoxifen can turn on nongenomic signaling acting on ER that resides at the membrane (M) and/or cytoplasm (a signaling mode also known as membrane-initiated steroid signaling, or MISS). This induction, in turn, through multiple interactions with signaling intermediate molecules such as Shc and MNAR, can activate growth factor (GF) tyrosine kinase receptors (TKRs), such as EGFR and HER2, and the IGFR and cellular kinases such as c-Src. Cytoplasmic signaling molecules such as metastasis-associated gene 1 (MTA1) can increase this non-nuclear fraction of ER. The interaction between membrane/cytoplasmic ER and TKRs turns on the TKR pathways and their downstream kinases, e.g., p42/44 MAPK and AKT. Other potential MISS activity involves the activation, either directly or indirectly, of G protein (GP)-coupled receptors (GPCRs), which can then trigger various signaling processes including the activation of c-Src and MMPs and subsequent cleavage and release of HB-EGF. The HB-EGF can then stimulate and activate the EGFR/2 signaling pathway. TKR-induced kinases phosphorylate (P) nuclear ER and its coactivators (CoA) as well as other transcription factors (TF), thus potentiating genomic ER activity, which results in enhanced gene expression including genes in the TKR pathways. These gene products in turn further augment GF-TKR signaling, thus completing the cooperative cycle between the two activities of ER and their crosstalk with the growth factor receptor and cellular kinase pathways. In the presence of excessive TKR signaling, such as in HER2-overexpressing tumors, the nongenomic rapid ER action may become more prominent. The resulting activation of downstream kinases can lead to endocrine resistance by modifying the activity of various transcription factors and/or negating the inhibitory effects of tamoxifen on nuclear ER. PKA, Protein kinase A.

Figure 3

Kaplan-Meier curves for disease-free survival (DFS) in tamoxifen-treated patients according to the HER family receptor and PgR status. Among tamoxifen-treated patients with ER+/PR+ tumors, neither EGFR (HER1) nor HER2 had a significant effect on DFS, although there was a suggestion of a trend in HER2-positive tumors. In contrast, among patients whose tumors were ER+/PR−, both EGFR and HER2 expression were associated with significantly poorer DFS (for HER-1, HR = 2.4, 95% CI = 1.0 to 5.4, P = 0.04; and for HER2, HR = 2.6, 95% CI = 1.1 to 6.0, P = 0.03). [Adapted with permission of Oxford University Press from Arpino et al. (147).]