Data from Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor Through cMYC Repression and Recruitment of the DREAM Complex

• DOI: 10.1158/0008-5472.c.6816209
• Publication Date: 2023-09-01T08:28:19Z
• Authors: Michael D. Nyquist; Ilsa M. Coleman; Jared M. Lucas; Dapei Li; Brian Hanratty; Hannah Meade; Elahe A. Mostaghel; Stephen R. Plymate; Eva Corey; Michael C. Haffner; Peter S. Nelson
• Keywords: E2F

<div>Abstract<p>The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. The AR represents a near-universal driver and therapeutic vulnerability metastatic cancer, targeting has remarkable index. Though most approaches directed toward focus on inhibiting signaling, laboratory now clinical data have shown that high dose, supraphysiological treatment (SPA) results growth repression improved outcomes subsets of cancer patients. A better understanding the mechanisms contributing to SPA response resistance could help guide patient selection combination therapies improve efficacy. To characterize we integrated metrics gene expression changes induced by together with cistrome protein-interactomes. These analyses indicated Dimerization partner, RB-like, E2F Multi-vulval class B (DREAM) complex mediates downregulation targets SPA. Notably, cancers complete genomic loss RB1 responded whereas DREAM components such as RBL1/2 promoted resistance. Overexpression MYC resulted attenuated SPA/AR-mediated target genes. findings support model SPA-mediated relies negative regulation leading E2F1 signaling via complex. integrity assembly may consequently serve determinants responses pathways mediating resistance.</p></div>