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.

Change in HER2 status after neoadjuvant chemotherapy and the prognostic impact in patients with primary breast cancer

“…Basic research studies have reported that heterogeneous tumors, such as ER‐positive/HER2‐positive tumors, are more resistant to chemotherapeutic agents . The mechanism of crosstalk between ER and HER2 may be associated with resistance to chemotherapy and changes in HER2 status . Another possible factor might be a different pCR rate after NAC according to ER status.…”

Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance

“…Most of these overlapping genes have an AP-1 motif in their promoter/enhancer regions. Interestingly, the upregulated overlapping genes belong to a network of GFRs, stress-related kinases, and signaling molecules activated by the microenvironment, all of which have been implicated in endocrine resistance [26]. These data suggest that AP-1, by engaging altered ER-dependent genomic networks, may act as a major node integrating diverse signaling pathways mediating endocrine resistance.…”

A Stromal Immune Module Correlated with the Response to Neoadjuvant Chemotherapy, Prognosis and Lymphocyte Infiltration in HER2-Positive Breast Carcinoma Is Inversely Correlated with Hormonal Pathways

“…There is increasing evidence to suggest that interactions between HER2 and hormone-receptor pathways play an important role in disease progression and that there is extensive, complex, bidirectional, crosstalk between the HER2 and ER pathways [44]. Immune signatures have been reported to have a predictive or prognostic role mostly in ER-negative breast cancers [45–48].…”