Bidirectional Crosstalk between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 Signaling Pathways in Breast Cancer: Molecular Basis and Clinical Implications

Abstract

The estrogen receptor (ER) and/or the human epidermal growth factor receptor 2 (HER2) signaling pathways are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. As a result, targeting these pathways provides the most effective therapies in appropriately selected patients. Nevertheless, resistance to both endocrine and anti-HER2 therapies occurs frequently and represents a major clinical challenge. Compelling preclinical and clinical evidence relates this treatment resistance to the presence of a complex bidirectional molecular crosstalk between the ER and HER2 pathways. As a consequence, treatment strategies targeting either pathway are associated with up-regulation of the other one, ultimately resulting in resistance to therapy. Therefore, a more promising strategy to prevent or overcome either endocrine or anti-HER2 resistance at least in some tumors is to combine targeted treatments that simultaneously block both signaling pathways. Many clinical trials exploring this strategy have shown positive results, and many more are currently ongoing. Future clinical trials with appropriate patient selection, based on biomarker evaluation of primary tumors and possibly of recurrent lesions, are warranted for the optimization of individualized therapeutic strategies.

Keywords: Crosstalk; Estrogen Receptor; HER2; Resistance.

Fig. 1

ER signaling, targeted therapies, and endocrine resistance. (A) ER signaling as dominant driver of cell proliferation and survival. The binding of estrogen to the ER protein results in its interaction with DNA, either directly at EREs of promoter/enhancer regions of target genes (classical nuclear genomic pathway) or indirectly by tethering to other transcription factors, including AP-1 and SP-1, at their DNA binding sites (non-classical nuclear genomic pathway). Estrogen-activated ER also interacts with coactivators (CoA) that facilitate its transcriptional activity. Ultimately, the transcription of ER target genes promotes cell proliferation, survival, and invasion. A small fraction of the cellular ER pool also resides at, or in proximity to, the plasma membrane, where it interacts with and promotes the activity of RTKs and other cellular kinases (non-nuclear/non-genomic pathway). Nuclear ER genomic activity is predominant in tumor cells with low growth factor receptor signaling and can be effectively inhibited by endocrine therapy with tamoxifen (T), fulvestrant (F), and Als. (B) Bidirectional crosstalk between the ER and HER pathways and resistance to endocrine therapy. In the presence of hyperactive HER signaling (such as in HER2+ tumors or in case of acquired overexpression of HER receptors during endocrine therapy), activated downstream kinases (e.g. Akt and MAPK) reduce ER expression at both the mRNA and protein levels. At the same time, these kinases phosphorylate ER and its coregulators, potentiating and modulating ER transcriptional activity and negating the effect of endocrine therapy. In addition, cytoplasmic/membrane ER non-genomic activity is increased, leading to further activation of the HER pathway by direct or indirect interaction with the HER receptors, G proteins, and other intracellular kinases. Non-nuclear/non-genomic ER activity can be stimulated rather than inhibited by tamoxifen. Collectively, these molecular events together contribute to intrinsic and acquired endocrine resistance.

Fig. 2

HER2 family pathways, targeted therapies, and treatment resistance. (A) HER signaling pathway as dominant driver of tumor cell growth and survival. Ligand-bound HER homo- and heterodimers, and HER2 homodimers in HER2+ tumors, activate downstream pathways (e.g. p42/44 MAPK and Akt), which in turn modulate the levels or activities of various transcription factors (TF) and their coregulators (such as coactivators, CoA). Activation of this core signaling process leads to changes in gene expression that ultimately mediate proliferation and survival stimuli. (B) ER signaling as mechanism of resistance to anti-HER2 therapy. Potent inhibition of the HER receptor layer by trastuzumab (T), lapatinib (L), pertuzumab (P), and trastuzumab-emtansine (T-DM1), as single agents or in combination, leads to effective blockade of downstream signaling, resulting in arrest of proliferation and induction of apoptosis. However, effective HER inhibition can lead to restoration/reactivation of ER signaling, which in turn provides alternative survival and proliferation stimuli leading to anti-HER2 resistance.