Longitudinal analysis of androgen deprivation of prostate cancer cells identifies pathways to androgen independence

BACKGROUND Following androgen ablation therapy, the majority of prostate cancer patients develop treatment resistance with a median time of 18–24 months to disease progression. METHODS To identify molecular targets that promote prostate cancer cell survival and contribute to androgen independence, we evaluated changes in LNCaP cell gene expression during 12 months of androgen deprivation. At time points reflecting critical growth and phenotypic changes, we performed Affymetrix expression array analysis to examine the effects of androgen deprivation during the acute response, during the period of apparent quiescence, and following the emergence of a highly proliferative, androgen‐independent prostate cancer cell phenotype (LNCaP‐AI). RESULTS We discovered alterations in gene expression for molecules associated with promoting prostate cancer cell growth and survival, and regulating cell cycle progression and apoptosis. Additionally, expression of AR co‐regulators, adrenal androgen metabolizing enzymes, and markers of neuroendocrine disease were significantly altered. CONCLUSIONS These findings contribute greatly to our understanding of androgen‐independent prostate cancer. The value of this longitudinal approach lies in the ability to examine gene expression changes throughout the adaptive response to androgen deprivation; it provides a more dynamic illustration of genes which contribute to disease progression in addition to specific genes which constitute an androgen‐independent phenotype. Prostate 68: 698–714, 2008. © 2008 Wiley‐Liss, Inc.