Mechanisms of resistance to endocrine therapy in breast cancer: focus on signaling pathways, miRNAs and genetically based resistance

Abstract

Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERα expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients.

Figure 1

Schematic representation of functional domains of human ERα and ERβ. The A/B domain at the N-terminal contains AF-1 site. The C domain includes the DNA-binding domain (DBD) and a dimerization site. The D domain contains a nuclear localization signal. The E/F domain is located at the C-terminal and comprises the ligand binding, as well as the AF-2 domain, a second nuclear localization signal, and another dimerization site.

Figure 2

Pathways involved in endocrine resistance. (a) While tamoxifen (T), aromatase inhibitors (AIs), or fulvestrant (F) inhibit estrogen (E) signalization, GFR pathways promote ER phosphorylation, transcription factors (TFs), and their coactivators (CoA) in a ligand-independent manner. E-ER complex outside the nucleus can interact with GFRs, Src, CoA and matrix metalloproteinases that release heparin-binding-EGF; (b) Stress may trigger signalization leading to ER and its coregulators phosphorylation; (c) Notch regulates the migration and invasion of breast cancer cells. E inhibits this pathway while T activates it; (d) High levels of CoA, low levels of corepressors (CoR) and altered expression of miRs (e) have been implicated in endocrine resistance development.