Cistrome analysis of YY1 uncovers a regulatory axis of YY1:BRD2/4-PFKP during tumorigenesis of advanced prostate cancer.

Castration-resistant prostate cancer (CRPC) is a terminal disease and the molecular underpinnings of CRPC development need to be better understood in order to improve its treatment. Here, we report that a transcription factor Yin Yang 1 (YY1) is significantly overexpressed during prostate cancer progression. Functional and cistrome studies of YY1 uncover its roles in promoting prostate oncogenesis in vitro and in vivo, as well as sustaining tumor metabolism including the Warburg effect and mitochondria respiration. Additionally, our integrated genomics and interactome profiling in prostate tumor show that YY1 and bromodomain-containing proteins (BRD2/4) co-occupy a majority of gene-regulatory elements, coactivating downstream targets. Via gene loss-of-function and rescue studies and mutagenesis of YY1-bound cis-elements, we unveil an oncogenic pathway in which YY1 directly binds and activates PFKP, a gene encoding the rate-limiting enzyme for glycolysis, significantly contributing to the YY1-enforced Warburg effect and malignant growth. Altogether, this study supports a master regulator role for YY1 in prostate tumorigenesis and reveals a YY1:BRD2/4-PFKP axis operating in advanced prostate cancer with implications for therapy.

Responsiveness of intrinsic subtypes to adjuvant anthracycline substitution in the NCIC.CTG MA.5 randomized trial.

PURPOSE: Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy. EXPERIMENTAL DESIGN: Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basal-like subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan-Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes. RESULTS: Intrinsic subtypes were associated with RFS (P = 0.0005) and OS (P < 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non-HER2-E tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined Her2(+) tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors [n = 94; HR, 1.1; 95% confidence interval (CI), 0.6-2.1 for RFS and HR, 1.3; 95% CI, 0.7-2.5 for OS]. CONCLUSION: HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required.

An integration of complementary strategies for gene-expression analysis to reveal novel therapeutic opportunities for breast cancer.

INTRODUCTION: Perhaps the major challenge in developing more effective therapeutic strategies for the treatment of breast cancer patients is confronting the heterogeneity of the disease, recognizing that breast cancer is not one disease but multiple disorders with distinct underlying mechanisms. Gene-expression profiling studies have been used to dissect this complexity, and our previous studies identified a series of intrinsic subtypes of breast cancer that define distinct populations of patients with respect to survival. Additional work has also used signatures of oncogenic pathway deregulation to dissect breast cancer heterogeneity as well as to suggest therapeutic opportunities linked to pathway activation. METHODS: We used genomic analyses to identify relations between breast cancer subtypes, pathway deregulation, and drug sensitivity. For these studies, we use three independent breast cancer gene-expression data sets to measure an individual tumor phenotype. Correlation between pathway status and subtype are examined and linked to predictions for response to conventional chemotherapies. RESULTS: We reveal patterns of pathway activation characteristic of each molecular breast cancer subtype, including within the more aggressive subtypes in which novel therapeutic opportunities are critically needed. Whereas some oncogenic pathways have high correlations to breast cancer subtype (RAS, CTNNB1, p53, HER1), others have high variability of activity within a specific subtype (MYC, E2F3, SRC), reflecting biology independent of common clinical factors. Additionally, we combined these analyses with predictions of sensitivity to commonly used cytotoxic chemotherapies to provide additional opportunities for therapeutics specific to the intrinsic subtype that might be better aligned with the characteristics of the individual patient. CONCLUSIONS: Genomic analyses can be used to dissect the heterogeneity of breast cancer. We use an integrated analysis of breast cancer that combines independent methods of genomic analyses to highlight the complexity of signaling pathways underlying different breast cancer phenotypes and to identify optimal therapeutic opportunities.