Androgen Receptor Function and Targeted Therapeutics Across Breast Cancer Subtypes

Emily A. Kolyvas; Carlos Caldas; Kathleen Kelly; Saif S. Ahmad


Breast Cancer Res. 2022;24(79) 

In This Article

AR and DNA Damage Repair

Steroid hormone receptors such as ER in BC are known to be involved in regulating the DNA damage response (DDR), and suppression of ER signalling with tamoxifen has been shown to augment RT response.[97–99] Goodwin et al. presented a mechanism by which this association between steroid hormones and DNA repair extends to AR activity in a PCa model.[100] In men with localized PCa, the standard of care is a combination of ADT with radiation, as the combination has been shown to be more effective than either treatment on its own.[101–103] AR activity allows for DNA DSB resolution, independent of cell cycling effects, by regulating some of the accessory factors necessary for DDR. AR acts as a transcriptional regulator of DDR factors, including DNA-PKcs, a kinase important in non-homologous end joining (NHEJ), to increase DNA repair and cell survival following DNA damage induction. Furthermore, DNA-PKcs then create a positive feedback circuit wherein AR is further activated to increase its transcription-activating potential.[100] Polkinghorn et al. confirmed this role of AR as a transcriptional regulator of DNA repair genes, and they showed that treatment with ADT decreases the expression of these genes.[104] Additional studies have also implicated a role for an AR-PARP1 signalling axis in breast cancer and have shown that combined inhibition of AR and PARP leads to enhanced antitumour activity by modulating the DDR.[105,106] The implications for a role of AR in DDR make it an interesting target for combination therapeutics with RT, as AR inhibition should potentiate radiation-induced damage in a tumour-selective manner. It should also be noted, however, that while AR signalling allows for damage repair, supraphysiological androgens are associated with the induction of DSBs.[107] For this reason, supraphysiological androgens are also under evaluation as a method of augmenting radiation response. This is actively being studied in PCa, and while it may be useful in BC, its use may be limited by side effects seen in previous studies with androgen agonists in BC.