Although recent studies have shown the importance of complex genomic rearrangements in prostate cancer initiation and progression, the mechanisms that generate these rearrangements are unknown. Our long-term goal is to understand the causes and consequences of these complex rearrangements in prostate and other cancers. The objective here is to determine the mechanism by which multiple, coordinate, double strand breaks (DSB) likely involved in generating these complex rearrangements can form. Our central hypothesis is that initiation of androgen-induced transcriptional programs in neoplastic prostate cells involves the formation of highly complex topological loops that are mediated in part by topoisomerase II beta (TOP2B);dysfunction of this enzyme can produce multiple simultaneous breaks that can recombine to form complex genomic rear- rangements. We have formulated this hypothesis on the basis of our strong preliminary data showing andro- gen-induced, TOP2B-mediated DSB that are recombinogenic and arise near rearrangement breakpoints ob- served in human prostate cancers. The rationale for this work is that understanding these mechanisms can inform strategies to prevent formation of these rearrangements, potentially allowing cancer prevention and interception, and may also spur development of rearrangement-based biomarkers for prostate cancer risk stratification. We will test our hypothesis through three specific aims: 1) Determine the role of TOP2B in chromosomal conformational remodeling during initiation of androgen receptor (AR) mediated transcriptional programs. 2) Identify the role of TOP2B binding and catalytic activity in generating androgen-induced double strand breaks and recombination/rearrangement events. 3) Determine the relevance and utility of a TOP2B-related rearrangement signature in human prostate cancer. To facilitate these aims, we have innovated and/or established feasibility in our hands for: i) robust methods for genetic and pharmacologic inhibition of TOP2B;ii) well defined prostate cancer cell line model systems to study androgen receptor signaling;iii) identification o rearrangement breakpoints in human prostate cancers with low-pass paired-end sequencing;iv) methods for measuring TOP2B-mediated chromosomal looping interactions, gene expression changes, DSB, and recombination events;and iv) powerful statistical methods for assessing the spatial correlations of these TOP2B- related events with each other and with rearrangement breakpoints identified in human cancers. Using such correlations with data collected here and with publically available data, we will be able to assess whether a TOP2B/AR rearrangement signature has relevance to human prostate cancer rearrangements and whether it can have utility for prostate cancer risk stratification. The approach is innovative and highly significant because it uses powerful new experimental and computational methodologies to test an innovative hypothesis explaining the formation of highly complex, context-specific rearrangements observed in human prostate cancer. This understanding can ultimately inform approaches for prostate cancer prevention and interception.
Prostate cancer causes substantial morbidity and mortality in adult men, and its initiation and disease progression are driven on a genetic level by chromosomal rearrangements, in addition to other abnormalities. This proposal is focused on understanding the molecular mechanisms involved in generating the chromosomal rearrangements. Such an understanding will allow development of strategies to prevent cancer progression, and may aid in the identification of chromosomal rearrangement profiles that can be used as biomarkers for prostate cancer risk stratification.
|Haffner, Michael C; Esopi, David M; Chaux, Alcides et al. (2017) AIM1 is an actin-binding protein that suppresses cell migration and micrometastatic dissemination. Nat Commun 8:142|
|Guo, Theresa; Sakai, Akihiro; Afsari, Bahman et al. (2017) A Novel Functional Splice Variant of AKT3 Defined by Analysis of Alternative Splice Expression in HPV-Positive Oropharyngeal Cancers. Cancer Res 77:5248-5258|
|Haffner, Michael C; Weier, Christopher; Xu, Meng Meng et al. (2016) Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization. J Pathol 238:31-41|
|Hubbard, Gretchen K; Mutton, Laura N; Khalili, May et al. (2016) Combined MYC Activation and Pten Loss Are Sufficient to Create Genomic Instability and Lethal Metastatic Prostate Cancer. Cancer Res 76:283-92|
|Mian, Omar Y; Khattab, Mohamed H; Hedayati, Mohammad et al. (2016) GSTP1 Loss results in accumulation of oxidative DNA base damage and promotes prostate cancer cell survival following exposure to protracted oxidative stress. Prostate 76:199-206|
|Hedayati, Mohammad; Haffner, Michael C; Coulter, Jonathan B et al. (2016) Androgen Deprivation Followed by Acute Androgen Stimulation Selectively Sensitizes AR-Positive Prostate Cancer Cells to Ionizing Radiation. Clin Cancer Res 22:3310-3319|