Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer

Abstract

Estrogen receptor α (ER) is the major driver of ∼75% of breast cancers, and multiple ER targeting drugs are routinely used clinically to treat patients with ER⁺ breast cancer. However, many patients relapse on these targeted therapies and ultimately develop metastatic and incurable disease, and understanding the mechanisms leading to drug resistance is consequently of utmost importance. It is now clear that, in addition to estrogens, ER function is modulated by other steroid receptors and multiple signaling pathways (e.g., growth factor and cytokine signaling), and many of these pathways affect drug resistance and patient outcome. Here, we review the mechanisms through which these pathways impact ER function and drug resistance as well as discuss the clinical implications.

Keywords: breast cancer; cross-talk; cytokines; estrogen receptor; growth factors.

Figure 1.

Activation of ER by phosphorylation induced by growth factor and cytokine signaling pathways. Estradiol can induce dimerization of ER and binding of the dimer to ER response elements (EREs) in chromatin, and, from these sites, ER drives a proproliferative gene program. In addition, multiple growth factor and cytokine signaling pathways can induce phosphorylation of ER at S167, S118, or S305, which can also activate the receptor and drive it onto chromatin in the absence of estradiol, thereby promoting cell proliferation.

Figure 2.

Redistribution of ER chromatin binding by other transcription factors. (A) Redistribution of ER binding to chromatin by progestogens and the cytokine TNFα through activation of progesterone receptor (PR) and NF-κB, respectively. (B) Modulation of ER binding and activity by glucocorticoids through activation of glucocorticoid receptor (GR).