Overcoming Endocrine Resistance in Breast Cancer

Abstract

Estrogen receptor-positive (ER⁺) breast cancer is the most common breast cancer subtype. Treatment of ER⁺ breast cancer comprises interventions that suppress estrogen production and/or target the ER directly (overall labeled as endocrine therapy). While endocrine therapy has considerably reduced recurrence and mortality from breast cancer, de novo and acquired resistance to this treatment remains a major challenge. An increasing number of mechanisms of endocrine resistance have been reported, including somatic alterations, epigenetic changes, and changes in the tumor microenvironment. Here, we review recent advances in delineating mechanisms of resistance to endocrine therapies and potential strategies to overcome such resistance.

Keywords: ESR1; SERD; SERM; aromatase inhibitor; breast cancer; endocrine resistance; estrogen receptor.

Figure 1:

Mechanism of action of endocrine therapies. (A) Ovaries, adrenal glands, adipose tissue, breast, and other tissues produce androgens which are converted to estrogens by aromatase. Upon binding to estrogen, the estrogen receptor (ER) dimerizes and translocates to the nucleus, where ER dimers bind coactivators (CoA) to form a transcriptionally active ER complex. (B) Non-steroidal, reversible aromatase inhibitors (AI) such as letrozole or anastrozole, or steroidal, irreversible AIs such as exemestane, block estrogen production by inhibiting the aromatization of androgens to estrogens. (C) Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene competitively inhibit the binding of estrogen to ER. SERM-bound ER dimers interact with the chromatin at estrogen response elements (ERE). However, SERM-bound ER dimers associate with co-repressors (CoR), which inhibit ER transcriptional activity in the breast. (D) Selective estrogen receptor downregulators (SERDs) such as fulvestrant are considered to be pure ER-antagonists. The inhibitory effect of SERDs was recently attributed to reduced ability of SERD-bound ER to translocate to the nucleus. Further, the ER-SERD complex is unable to establish an open chromatin conformation to facilitate transcription of ER-regulated genes. SERD-bound ER undergoes degradation as a consequence of impaired mobility. (E) Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that consist of a ligand for ER and another ligand which serves as a substrate for the E3 ubiquitin ligase complex. Upon binding to ER, PROTACs recruit the E3 ubiquitin ligase complex which polyubiquitilate ER and mark it for proteasomal degradation.

Figure 2:

Activation of HER2, EGFR, FGFR, and other RTKs promotes endocrine resistance. Aberrant activation of RTKs (most commonly by mutation or amplification) augment PI3K and MAPK signaling, which induce ER phosphorylation and promote ligand-independent ER activation. Loss-of-function mutations in NF1 constitutively activates Ras, which can further activate PI3K and MAPK pathways. Phosphorylation of ER promotes transcription of ER-regulated genes in a ligand-independent manner. CCND1, the gene encoding for cyclin D1, is a major target of both ER and oncogenic RTK signaling. In addition to ER, RTKs activate other transcription factors that promote ER-independent survival. RTK-mediated endocrine resistance could be potentially overcome by the combination of an ER antagonist and corresponding RTK inhibitor ± CDK4/6 inhibitor.

Figure 3:

Mechanisms of endocrine resistance and potential therapeutic strategies to combat resistance. SERD, selective estrogen receptor downregulator; SERCA, selective estrogen receptor covalent antagonist; PROTAC, proteolysis targeting chimera; TKI, tyrosine kinase inhibitor; ICI, immune checkpoint inhibitor