Androgen receptor and estrogen receptor variants in prostate and breast cancers

Abstract

The androgen receptor (AR) and estrogen receptor alpha (ERα) are steroid receptor transcription factors with critical roles in the development and progression of prostate and breast cancers. Advances in the understanding of mechanisms underlying the ligand-dependent activation of these transcription factors have contributed to the development of small molecule inhibitors that block AR and ERα actions. These inhibitors include competitive antagonists and degraders that directly bind the ligand binding domains of these receptors, luteinizing hormone releasing hormone (LHRH) analogs that suppress gonadal synthesis of testosterone or estrogen, and drugs that block specific enzymes required for biosynthesis of testosterone or estrogen. However, resistance to these therapies is frequent, and is often driven by selection for tumor cells with alterations in the AR or ESR1 genes and/or alternatively spliced AR or ESR1 mRNAs that encode variant forms AR or ERα. While most investigations involving AR have been within the context of prostate cancer, and the majority of investigations involving ERα have been within the context of breast cancer, important roles for AR have been elucidated in breast cancer, and important roles for ERα have been elucidated in prostate cancer. Here, we will discuss the roles of AR and ERα in breast and prostate cancers, outline the effects of gene- and mRNA-level alterations in AR and ESR1 on progression of these diseases, and identify strategies that are being developed to target these alterations therapeutically.

Keywords: AR; Androgen receptor; Breast cancer; DNA alterations; ESR1; Estrogen receptor; Prostate cancer; Splice variants.

Figure 1.. Androgen Receptor Alterations.

A. Shows AR gene rearrangements leading to the synthesis of AR-V12. B. Shows the effect of AR gene and/or enhancer amplification and the increase of AR protein levels. C. AR amplification through extrachromosomal DNA leads to increased AR protein levels. Pink box with letter “B” represents an event detected in BCa. Blue box with letter “P” represents an event detected in PCa. D. Schematic of the AR gene exon organization and the resulting AR protein with the corresponding domains. AR-V7 and AR-V9 are also shown as truncated forms of full-length AR. Legend: CE3: cryptic exon 3; CE5: cryptic exon 5; AR: androgen receptor; NTD: n-terminal domain; DBD: DNA binding domain; H: hinge domain; LBD: ligand binding domain; P: present in prostate cancer; B: present in breast cancer; ecDNA: extrachromosomal DNA.

Figure 2.. Estrogen Receptor Alpha Alterations

A. ESR1 gene exons and the resulting protein with the corresponding domains. ER-α46, ER-α36 and ER-α30 are also shown. B. Amplifications of the ESR1 gene lead to an increase in the synthesis of ERα proteins. C. ESR1 gene fusions result in fused proteins with diverse effects in cellular growth. Legend: ER: estrogen receptor; NTD: n-terminal domain; DBD: DNA binding domain; H: hinge domain; LBD: ligand binding domain; AF-1: activation function domain 1; AF-2: activation function domain 2; P: present in prostate cancer; B: present in breast cancer.