Androgen Effects on Amyloid Precursor Protein Processing Pathways in Cancer: A Systematic Review

Androgens have been shown to be linked to cancer progression, particularly in hormone-dependent cancers such as prostate and breast cancer, but also other cancers. Amyloid precursor protein (APP), which has primarily been studied in Alzheimer's disease, is gaining recognition for its role in tumor growth and survival. While APP overexpression and androgen receptor (AR) signaling are each associated with cancer progression, the connection between androgens and APP processing in cancer has not been thoroughly investigated. This systematic review was conducted through a comprehensive search of PubMed, Scopus, Web of Science, and EMBASE between 2000 to 2024 for studies examining the effects of androgens on APP and its cleavage enzymes in cancer. Five experimental studies met the inclusion criteria, covering prostate and breast cancer models. Data were extracted and synthesized narratively due to heterogeneity in methods and outcomes. Three studies reported that dihydrotestosterone (DHT) or AR agonists increased the expression and nuclear translocation of ADAM10, a key α-secretase enzyme in the non-amyloidogenic APP processing pathway. Two studies identified APP as an androgen-responsive gene, showing that androgens upregulated APP expression in prostate and breast cancer cells and promoted the proliferation of cancer cells. Inhibition or knockdown of APP and ADAM10 reduced proliferation, supporting their roles in tumor progression. Androgen signaling modulates APP processing in cancer, particularly through the non-amyloidogenic pathway; however, significant knowledge gaps remain. Further studies are needed to explore the interaction between androgens and APP processing in other cancer types, as well as to elucidate downstream signaling pathways regulated at the gene expression level.