Endocrine therapy resistance in breast cancer: current status, possible mechanisms and overcoming strategies

Abstract

Endocrine therapy has become one of most effective forms of targeted adjuvant therapy for hormone-sensitive breast cancer and may be given after surgery or radiotherapy, and also prior, or subsequent to chemotherapy. Current commonly used drugs for adjuvant endocrine therapy can be divided into following three classes: selective estrogen receptor modulators, aromatase inhibitors and selective estrogen receptor downregulators. Tumor cells can develop resistance to endocrine therapy, a major obstacle limiting the success of breast cancer treatment. The complicated crosstalk, both genomic and nongenomic, between estrogen receptors and growth factors was considered to be a crucial factor contributing to endocrine resistance. However, resistance to this therapy is thought to be a progressive, step-wise process, and the underlying mechanism remains unclear. In this review, we summarize the possible biological and molecular mechanisms that underlie endocrine resistance, and discuss some novel strategies to overcoming these issues.

Keywords: breast cancer; drug resistance; endrocrine therapeutics; estrogen receptor.

Figure 1.. Classical and nonclassical and legend-independent mode of nuclear-initiated steroid signaling.

ER, in its classical mode action (A), directly binds to specific DNA response elements called EREs. Estrogen(E2)-bound ER generally recruits CoA complexes to induce gene transcription. In ERs nonclassical mode action (B), ER regulates gene transcription through protein–protein interactions (e.g., with Fos/Jun family members) with other transcription factors, particularly members of the Ap-1 families. In contrast to estrogen-dependent manner of ER action, ER signaling can be activated by phosphorylation at specific ER sites (C). Together, all of these nuclear ER genomic activities are called nuclear-initiated steroid signaling. CoA: Coactivator; ER: Estrogen receptor; ERE: Estrogen response element.

Figure 2.. Integration of genomic and nongenomic ER action and its crosstalk with growth factor receptor pathways in breast cancer: a working model.

In ER-positive breast tumors, genomic ER activity meditated by nuclear-initiated steroid signaling always predominates (see Figure 1), although some nongenomic signaling on acting ER that resides at the membrane and/or cytoplasm also occurs. This situation is usually upon acquisition of tamoxifen resistance or adaptation to hormone deprivation. Therefore, several tyrosine kinase receptors such as HER2 and EGFR as well as IGFR signaling become activated. Tyrosine kinase receptor-induced kinases phosphorylate nuclear ER and its CoA, thus promoting genomic ER activity and enhancing gene expression. As a result, genomic and nongenomic activities of ER and their crosstalk with growth factor tyrosine kinase pathways cooperative in promoting gene transcription, thus leading to endocrine resistance. Targeting the growth factor receptor pathway at different nodal points using antibodies (trastuzumab) and tyrosine kinase inhibitors (gefitinib, erlotinib and lapatinib) or other signal transduction inhibitors (e.g., mTOR inhibitors and MEK inhibitors) can eliminate the molecular crosstalk and overcome endocrine resistance. CoA: Coactivator; ER: Estrogen receptor; ERE: Estrogen response element. Adapted with permission from [10].