Regulation of Cellular Plasticity by Androgen Receptor Splicing Variant in Prostate Cancer
Abstract
One in nine men will be diagnosed with prostate cancer in his lifetime. Understanding the mechanisms underlying regulation of the androgen receptor (AR) activity is critical for the development of effective treatment for incurable castration-resistant prostate cancer (CRPC) and, optimally, reducing or delaying lethality in Veterans who suffer from prostate cancer. We and others previously discovered several AR splicing variants lacking the ligand-binding domain in hormone-refractory prostate cancer cells. One major splicing variant, AR3 (also known as AR-v7), is upregulated during prostate cancer progression, and its expression level predicts the risk of tumor recurrence and enzalutamide resistance. This project aims to elucidate the role of androgen receptor splicing variant (AR3/AR-v7) in the therapeutic resistance of prostate cancer. The precise mechanisms by which AR3 regulates transcription program in prostate cancer cells and its role in transition to more aggressive neuroendocrine prostate cancer (NEPC) remain to be fully understood. Our recent study showed that the AR3 splicing variant, but not the prototype full-length AR (AR-FL), positively regulates transcription factor E2F1 expression in prostate cancer cells resistant to both Enzalutamide and Docetaxel. E2F1 in turn regulates AR3 expression, and these two proteins form a positive regulatory feed-forward loop. These findings suggest that AR3 may play a distinct, yet essential, role in disease progression and drug response through regulating a unique set of genes that are not regulated by the prototype AR. We have identified a number of proteins preferentially binding to AR3 through a proteomic analysis. We will delineate the mechanisms by which AR3 exerts its transcriptional activity and specificity in prostate cancer cells and test the effects of miR-877 on blocking AR3 activity on drug sensitivity (Aim 1). In addition, we have established a new transgenic mouse model, fAR3pTG, by targeted expression of AR3 in prostatic epithelium to recapitulate pathological changes occurring in human prostate cancer. RNA-seq analysis on fAR3pTg prostate reveals that multiple genes involved in neuroendocrine differentiation (NED) and metastasis processes are altered. We will establish a compound mouse model and examine the role of AR3 in NED and prostate cancer metastasis in Pten-deficient background (Aim 2). Successful completion of the proposed research will enable us to gain new insights into molecular mechanisms underlying prostate cancer metastasis and therapeutic resistance, as well as to develop new effective therapeutics targeting AR variants to optimally reduce or delay lethality for patients who suffer from prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310142
Entities
People
- Yun Qiu
Organizations
- United States Army
- University of Maryland, Baltimore