The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC.

Background Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31 and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans refined previous association signals by utilizing the reduced linkage disequilibrium observed in African-Americans. Methods 1308 African-American cases and 1241 African-American controls from three centers were genotyped for 760 single nucleotide polymorphisms spanning three regions, and additional SNP imputation was performed. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate. Results The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution (rs16969968: OR = 1.57, 95% CI = 1.25–1.97, P = 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology-specific and included a missense variant in BAT2 associated with squamous-cell carcinoma (rs2736158: OR = 0.64, 95% CI = 0.48–0.85, P = 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR = 0.82, 95% CI = 0.73–0.93, P = 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR = 0.75, 95% CI = 0.65–0.86, P = 8.1 × 10−5). Conclusions Polymorphisms in 5p15.33, 6p22.1-p21.31 and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous-cell carcinoma. Impact Results implicate the BAT2, TERT and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.

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Hormone-dependent cancers present a significant public health challenge, as they are among the most common cancers in the world. One factor associated with cancer development and progression is metabolic reprogramming. By understanding these alterations, we can identify potential markers and novel biochemical therapeutic targets. Metabolic profiling is an advanced technology that allows investigators to assess low molecular weight compounds that reflect physiological alterations. Current research in metabolomics in prostate and breast cancer has made great strides in uncovering specific metabolic pathways that are associated with cancer development, progression, and resistance. This review will highlight some of the major findings and potential therapeutic advances that have been reported utilizing this technology.

Background: Given the scarcity of cell lines from underrepresented populations, it is imperative that genetic ancestry for these cell lines is characterized. Consequences of cell line mischaracterization include squandered resources and publication retractions. Methods: We calculated genetic ancestry proportions for 15 cell lines to assess the accuracy of previous race/ethnicity classification and determine previously unknown estimates. DNA was extracted from cell lines and genotyped for ancestry informative markers representing West African (WA), Native American (NA), and European (EUR) ancestry. Results: Of the cell lines tested, all previously classified as White/Caucasian were accurately described with mean EUR ancestry proportions of 97%. Cell lines previously classified as Black/African American were not always accurately described. For instance, the 22Rv1 prostate cancer cell line was recently found to carry mixed genetic ancestry using a much smaller panel of markers. However, our more comprehensive analysis determined the 22Rv1 cell line carries 99% EUR ancestry. Most notably, the E006AA-hT prostate cancer cell line, classified as African American, was found to carry 92% EUR ancestry. We also determined the MDA-MB-468 breast cancer cell line carries 23% NA ancestry, suggesting possible Afro-Hispanic/ Latina ancestry. Conclusions: Our results suggest predominantly EUR ancestry for the White/Caucasian-designated cell lines, yet high variance in ancestry for the Black/African Americandesignated cell lines. In addition, we revealed an extreme misclassification of the E006AA-hT cell line. Impact: Genetic ancestry estimates offer more sophisticated characterization leading to better contextualization of findings. Ancestry estimates should be provided for all cell lines to avoid erroneous conclusions in disparities literature.

African American (AA) men have a 60% higher incidence and two times greater risk of dying of prostate cancer (PCa) than European American men, yet there is limited insight into the molecular mechanisms driving this difference. To our knowledge, metabolic alterations, a cancer-associated hallmark, have not been reported in AA PCa, despite their importance in tumor biology. Therefore, we measured 190 metabolites across ancestry-verified AA PCa/benign adjacent tissue pairs (n = 33 each) and identified alterations in the methionine-homocysteine pathway utilizing two-sided statistical tests for all comparisons. Consistent with this finding, methionine and homocysteine were elevated in plasma from AA PCa patients using case-control (AA PCa vs AA control, methionine: P = .0007 and homocysteine: P < .0001), biopsy cohorts (AA biopsy positive vs AA biopsy negative, methionine: P = .0002 and homocysteine: P < .0001), and race assignments based on either self-report (AA PCa vs European American PCa, methionine: P = .001, homocysteine: P < .0001) or West African ancestry (upper tertile vs middle tertile, homocysteine: P < .0001; upper tertile vs low tertile, homocysteine: P = .002). These findings demonstrate reprogrammed metabolism in AA PCa patients and provide a potential biological basis for PCa disparities.

This study suggests that lower urinary 2:16 OHE ratios are predictors of breast cancer risk. Profiling estrogen metabolites may identify women who are more probably to develop breast cancer within a population of women with known risk factors and may help to further elucidate the clinical relevance of urinary 2:16 OHE ratios as clinical markers and prognostic indicators in this population.

African American cancer patients have higher mortality rates and shorter survival times compared with European American patients (1-5). In the United States, for every 100,000 cancer patients, the age-adjusted cancer-associated mortality for African American versus European American patients was 189.54 and 163.54 respectively, resulting in a disparity ratio of 13.87 % (2-5). When examined for individual tumor types, the disparity in mortality was higher in African American patients for cancers of the breast, colon, rectum, uterus, liver, lung, bronchus, and prostate with disparity ratios ranging from 6.41% (for lung cancer across both sexual phenotypes) to 118.52 % (for men with prostate cancer [PCa]). This observation is consistent with the 5-and 10-year survival data obtained from the Surveillance Epidemiology and End Results database (Supplemental Table 1; supplemental material available online with this article; BACKGROUND. African American patients have higher cancer mortality rates and shorter survival times compared with European American patients. Despite a significant focus on socioeconomic factors, recent findings strongly argue the existence of biological factors driving this disparity. Most of these factors have been described in a cancer-type specific context rather than a pan-cancer setting.