Cancer Stem Cells and Androgen Receptor Signaling: Partners in Disease Progression

Abstract

Cancer stem cells exhibit self-renewal, tumorigenesis, and a high differentiation potential. These cells have been detected in every type of cancer, and different signaling pathways can regulate their maintenance and proliferation. Androgen receptor signaling plays a relevant role in the pathophysiology of prostate cancer, promoting cell growth and differentiation processes. However, in the case of prostate cancer stem cells, the androgen receptor negatively regulates their maintenance and self-renewal. On the other hand, there is evidence that androgen receptor activity positively regulates the generation of cancer stem cells in other types of neoplasia, such as breast cancer or glioblastoma. Thus, the androgen receptor role in cancer stem cells depends on the cellular context. We aimed to analyze androgen receptor signaling in the maintenance and self-renewal of different types of cancer stem cells and its action on the expression of transcription factors and surface markers associated with stemness.

Keywords: androgen receptor; breast cancer; cancer stem cell; glioblastoma; prostate cancer.

Figure 1

Androgen receptor signaling in cancer stem cells. (a) Testosterone, due to its hydrophobic characteristics, crosses the cell membrane ①. Once in the cytoplasm, it can be metabolized into DHT ② or directly bind to the AR ③. The interaction of the AR with its ligand generates conformational changes that release it from heat shock proteins ④ that keep it stable in the cytoplasm and protect it from degradation. Once the AR is bound to its ligand, it can be phosphorylated ⑤ and subsequently form a homodimer ⑥, which can translocate to the nucleus and recognize specific gene sequences ⑦. (b) The activated AR in CSCs may promote the expression of genes associated with stemness. However, its effects on self-renewal, differentiation, and tumorigenic capacity seem to depend on the tumor context. Created with Biorender.com.