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Hung-Ming Lam, Bin Ouyang, Jing Chen, Jun Ying, Jiang Wang, Chin-Lee Wu, Li Jia, Mario Medvedovic, Robert L Vessella, and Shuk-Mei Ho

Castration-resistant prostate cancer (CRPC) is an advanced-stage prostate cancer (PC) associated with high mortality. We reported that G-1, a selective agonist of G protein-coupled receptor 30 (GPR30), inhibited PC cell growth by inducing G2 cell cycle arrest and arrested PC-3 xenograft growth. However, the therapeutic actions of G-1 and their relationships with androgen in vivo are unclear. Using the LNCaP xenograft to model PC growth during the androgen-sensitive (AS) versus the castration-resistant (CR) phase, we found that G-1 inhibited growth of CR but not AS tumors with no observable toxicity to the host. Substantial necrosis (approximately 65%) accompanied by marked intratumoral infiltration of neutrophils was observed only in CR tumors. Global transcriptome profiling of human genes identified 99 differentially expressed genes with ‘interplay between innate and adaptive immune responses’ as the top pathway. Quantitative PCR confirmed upregulation of neutrophil-related chemokines and inflammation-mediated cytokines only in the G-1-treated CR tumors. Expression of murine neutrophil-related cytokines also was elevated in these tumors. GPR30 (GPER1) expression was significantly higher in CR tumors than in AS tumors. In cell-based experiments, androgen repressed GPR30 expression, a response reversible by anti-androgen or siRNA-induced androgen receptor silencing. Finally, in clinical specimens, 80% of CRPC metastases (n=123) expressed a high level of GPR30, whereas only 54% of the primary PCs (n=232) showed high GPR30 expression. Together, these results provide the first evidence, to our knowledge, that GPR30 is an androgen-repressed target and G-1 mediates the anti-tumor effect via neutrophil-infiltration-associated necrosis in CRPC. Additional studies are warranted to firmly establish GPR30 as a therapeutic target in CRPC.

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Vasily N Aushev, Kalpana Gopalakrishnan, Susan L Teitelbaum, Humberto Parada Jr, Regina M Santella, Marilie D Gammon, and Jia Chen

Environmental phenols and phthalates are common ingredients in personal care products and some have been implicated in breast cancer progression. We have previously identified genes differentially expressed in response to low-dose exposure to diethyl phthalate (DEP) and methyl paraben (MPB) in a rat model. Herein we explore if these genes are associated with breast cancer mortality in humans. We profiled MPB- and DEP-responsive genes in tumors by NanoString® from a population-based cohort of 606 women with first primary breast cancer among whom 119 breast cancer-specific deaths occurred within 15+ years of follow-up. For each gene, Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results were validated in two publicly available datasets. The following results were obtained. From 107 DEP- and 77 MPB-responsive genes profiled, 44 and 30 genes, respectively, were significantly associated with breast cancer-specific mortality. Some top DEP-responsive genes are novel for breast cancer mortality, such as ABHD14B (for high-vs-low expression, HR 0.36, 95% CI: 0.2–0.5) and TMC4 (HR 0.37, 95% CI: 0.3–0.5); top hits for MPB (SLC40A1 (HR 0.37, 95% CI: 0.3–0.5) and NTN4 (HR 0.39, 95% CI: 0.3–0.6)) are well-known predictors of breast cancer survival. PLEKHA6 was another novel survival predictor, sensitive to hormonal receptor status (HR 0.5, 95% CI 0.3–0.9 for hormonal receptor-positive and HR 3.2, 95% CI 1.7–6.2 for -negative group). In conclusion, tumor expression of DEP- and MPB-responsive genes is associated with breast cancer mortality, supporting that exposure to these chemicals may influence the progression of breast cancer.

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Bo Chen, Guochun Zhang, Guangnan Wei, Yulei Wang, Liping Guo, Jiali Lin, Kai Li, Hsiaopei Mok, Li Cao, Chongyang Ren, Lingzhu Wen, Minghan Jia, Cheukfai Li, Ting Hou, Han Han-Zhang, Jing Liu, Charles M Balch, and Ning Liao

HER2-positive breast cancer is a biologically and clinically heterogeneous disease. Based on the expression of hormone receptors (HR), breast tumors can be further categorized into HR positive and HR negative. Here, we elucidated the comprehensive somatic mutation profile of HR+ and HR− HER2-positive breast tumors to understand their molecular heterogeneity. In this study, 64 HR+/HER2+ and 43 HR-/HER2+ stage I-III breast cancer patients were included. Capture-based targeted sequencing was performed using a panel consisting of 520 cancer-related genes, spanning 1.64 megabases of the human genome. A total of 1119 mutations were detected among the 107 HER2-positive patients. TP53, CDK12 and PIK3CA were the most frequently mutated, with mutation rates of 76, 61 and 49, respectively. HR+/HER2+ tumors had more gene amplification, splice site and frameshift mutations and a smaller number of missense, nonsense and insertion-deletion mutations than HR-/HER2+ tumors. In KEGG analysis, HR+/HER2+ tumors had more mutations in genes involved in homologous recombination (P = 0.004), TGF-beta (P = 0.007) and WNT (P = 0.002) signaling pathways than HR-/HER2+ tumors. Moreover, comparative analysis of our cohort with datasets from The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium revealed the distinct somatic mutation profile of Chinese HER2-positive breast cancer patients. Our study revealed the heterogeneity of somatic mutations between HR+/HER2+ and HR-/HER2+ in Chinese breast cancer patients. The distinct mutation profile and related pathways are potentially relevant in the development of optimal treatment strategies for this subset of patients.