Min-Yu Ko

The androgen receptor (AR) regulates processes in prostate cancer (PCa); drugs targeting it are the cornerstone of therapeutic interventions for this disease. In probing the pharmacology of AR in PCa, we found that classical androgen responses, used for therapy development, are controlled by agonist-induced AR dimers. This dimeric form’s transcriptional program affects differentiation more than PCa pathobiology. Surprisingly, low androgen levels, like intratumoral production, trigger non-genomic mammalian target of rapamycin (mTOR) activation via monomeric AR. This boosts mRNA translation for cell cycle/DNA repair, increasing proliferation. These findings pinpoint AR’s role in PI3K/mTOR signaling, vital for PCa cell growth. Since mTOR inhibitors are toxic with modest metastatic PCa efficacy, underscoring the need for new AR(monomer)/mTOR axis intervention approaches – is this proposal’s key goal.