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Yue-Yu Shi,1 Xing-Lei Chen,1 Qian-Xin Chen,1 Yuan-Zhong Yang,2 Meng Zhou,1 Yue-Xiang Ren,3 Lu-Ying Tang,3 Ze-Fang Ren1 1School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2The Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 3The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Ze-Fang Ren, School of Public Health, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, People’s Republic of China, Tel/Fax +86-20-87332577, Email renzef@mail.sysu.edu.cn Lu-Ying Tang, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong, People’s Republic of China, Tel +86-20-85253000, Fax +86-20-85253336, Email tangly@mail.sysu.edu.cnPurpose: Enolase-1 (ENO1) plays a key role in malignancies. Previous studies on the association between ENO1 expression and breast cancer prognosis had yielded inconsistent results. In the present study, we assessed the prognostic effect of ENO1 in breast cancer using Guangzhou Breast Cancer Study (GZBCS) cohort with full consideration of the potential confounders and the modification effects. The results were further validated in the TCGA-BRCA cohort and explained by tumor immunity.Methods: ENO1 protein expressions were evaluated by immunohistochemistry in tissue microarrays from 961 patients with primary invasive breast cancer. Chi-square tests were used to assess the association of ENO1 levels with the patient’s characteristics. Cox regression models were applied to assess the prognostic effects. The TCGA-BRCA cohort was utilized to validate the results and explore the potential mechanisms. The immune infiltration was determined using the CIBERSORT and ssGSEA algorithms; the correlation between ENO1 expression and the abundance of tumor-infiltrating immune cells (TIICs) and scores of immune-related functions was evaluated by Wilcoxon signed-rank tests and Spearman’s rank test.Results: ENO1 protein expression exerted a protective effect on OS in stage I/II patients (HR=0.58, 95% CI: 0.35– 0.96) but not in stage III patients (HR=1.42, 95% CI: 0.81– 2.49, P interaction=0.04) in GZBCS; consistent results were obtained at mRNA levels in TCGA cohort. Immune infiltration analyses revealed that ENO1 was positively correlated with multiple antitumor TIICs (including M1 macrophages, B cells, CD8 T cells, T helper 2 cells, and NK cells) only in stage I/II but not stage III patients.Conclusion: A higher expression of ENO1 was associated with a better prognosis only in early-stage breast cancer, which may be related to the different effects of ENO1 on immune infiltration, suggesting that ENO1 may be a promising target for precision immunotherapy in breast cancer.Keywords: ENO1, breast cancer, prognosis, tissue microarray, tumor-infiltrating immune cells

Background: Previous studies have found that acute febrile infection may decrease the risk of breast cancer. Meanwhile, it is well known that interleukin-6 (IL6) played dual roles in the tumor microenvironment. Fever may stimulate IL6 production, and IL6 rs1800796 also influences the expression of IL6. However, the impact of fever and its interaction with IL6 rs1800796 on breast cancer survival remains to be explored. Methods: This was a prospective cohort study of 4,223 breast cancer patients. Exposures were pre-/postdiagnostic infection-induced fever and rs1800796 polymorphism. The endpoints were overall survival (OS) and progression-free survival (PFS). Adjusted hazard ratios were obtained using multivariate Cox proportional hazards regression models. Results: Compared with women without prediagnostic fever, the adjusted hazard ratio (HR) of progression for those with prediagnostic fever was 0.81 (95% CI, 0.66–0.99), particularly for the CC genotype of IL6 rs1800796 (HR, 0.53; 95% CI, 0.36–0.79). OS was also better (HR, 0.59; 95% CI, 0.36–0.99) among women with the CC genotype exposed to prediagnostic fever, accompanied by a significant interaction (P = 0.021). Postdiagnostic fever conferred better PFS for breast cancer (HR, 0.72; 95% CI, 0.52–1.00). Irrespective of the genotype of IL6, lymph node–positive women with postdiagnostic fever (HR, 0.57; 95% CI, 0.37–0.89) had a lower risk of progression than lymph node–negative women (HR, 1.12; 95% CI, 0.70–1.79). Conclusions: Infection-induced fever was beneficial to breast cancer survival, particularly for women who were the CC genotype of IL6 rs1800796 or node positive. Impact: This study provides new insight into the roles of infection-induced fever as a potential prognostic marker and therapy regimen for breast cancer.

Background Cellular experiments revealed that a decreased histone H3 lysine 9 trimethylation (H3K9me3) level was associated with the upregulation of oncogenes in breast cancer cells. Moreover, the role of H3K9me3 in breast cancer was closely associated with estrogen receptor (ER) status. Therefore, we aimed to examine the prognostic value of H3K9me3 on breast cancer by ER status. The level of H3K9me3 in tumors were evaluated with tissue microarrays by immunohistochemistry for 917 women diagnosed with primary invasive breast cancer. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were estimated using Cox regression models. Interaction between H3K9me3 and ER on the prognosis was assessed on multiplicative scale. Results The level of H3K9me3 in tumor tissues was lower than that in adjacent tissues. The high level of H3K9me3 was associated with a better OS (HR = 0.43, 95% CI: 0.21–0.86) and PFS (HR = 0.49, 95% CI: 0.29–0.81) among only ER-positive but not ER-negative tumors. Moreover, the interaction between the level of H3K9me3 and ER status (negative and positive) on the prognosis was significant (Pinteraction = 0.011 for OS; Pinteraction = 0.022 for PFS). Furthermore, the ER-positive tumors were stratified by ER-low and ER-high positive tumors, and the prognostic role of H3K9me3 was significant among only ER-high positive patients (HR = 0.34, 95% CI: 0.13–0.85 for OS; HR = 0.47, 95% CI: 0.26–0.86 for PFS). Conclusions Our study showed that the prognostic value of H3K9me3 on breast cancer was related to ER status and expression level, and the high level of H3K9me3 was associated with a better prognosis among ER-positive tumors, particularly ER-high positive tumors.

Reproductive factors associated with breast cancer risk may also affect the prognosis. This study aimed to evaluate the associations of multiple reproductive factors with breast cancer prognosis and the modifying effects of menopausal status. We obtained data from 3805 breast cancer patients recruited between October 2008 and June 2016 in Guangzhou. The subjects were followed up until 30 June 2018. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated using multivariate Cox models to estimate the associations. It was found that there were U‐shaped patterns for the associations of age at first birth and durations from first/last birth to diagnosis with breast cancer prognosis. The adverse effects of old age at first birth [>30 years vs 23‐30 years, HR (95% CI): 1.59 (1.01‐2.50)] and long intervals from first [≥20 years vs 10‐19 years, HR (95% CI): 1.55 (1.07‐2.27)] or last [≥20 years vs 10‐19 years, HR (95% CI): 1.63 (1.08‐2.46)] birth to diagnosis on progression‐free survival (PFS) were significantly more pronounced among premenopausal women. Additionally, long interval (>5 years) between first and second birth was associated with a better PFS [HR (95% CI): 0.64 (0.42‐0.97)]. These results suggested that age at first birth, durations from first/last birth to diagnosis, and intervals between first and second birth should be taken into account when following the patients and assessing the prognosis of breast cancer, particularly for premenopausal patients. These findings would also have implications for further insight into the mechanisms of breast cancer development., This study found U‐shaped patterns for the associations of age at first birth and durations from first/last birth to diagnosis with breast cancer prognosis, particularly for premenopausal women; a relatively long interval between first and second birth may benefit prognosis of breast cancer.

Purpose This study differentiates patient and care delays of breast cancer and explores the related factors as well as the associations with the prognosis in Guangzhou, a southern city of China. Methods A cohort of female incident breast cancer patients (n=1,551) was recruited from October 2008 to March 2012 and followed up until January 1, 2016 (n=1,374) in the affiliated hospitals of Sun Yat-sen University. The factors associated with patient and care delays were analyzed with multivariable logistic models. Cox proportional hazards regression models were constructed to estimate the impacts of the delays on the prognosis. Results There were 40.4% patient delay (≥3 months) and 15.5% care delay (≥1 month). The patient delay, but not the care delay, was significantly related to the clinical stage and consequently worsened the prognosis of breast cancer (hazard ratio, 1.45; 95% confidence interval, 1.09 to 1.91 for progression-free survival). The factors related to an increased patient delay included premenopausal status, history of benign breast disease, and less physical examination. Conclusion Patient delay was the main type of delay in Guangzhou and resulted in higher clinical stage and poor prognosis of breast cancer. Screening for breast cancer among premenopausal women may be an effective way to reduce this delay.

Cadmium (Cd) has been confirmed to be associated with breast carcinogenesis, but the mechanism was not clarified yet. Given that epigenetic modification was speculated as underlying mechanism, we examined the differential epigenome caused by Cd in breast cancer cells. Profiles of DNA methylation, microRNA (miRNA), long non-coding RNA (lncRNA), and message RNA (mRNA) were derived from Cd-treated and untreated MCF-7 breast cancer cells by microarray. We identified 997 target genes epigenetically regulated by Cd through cross-verification with the differential epigenome and transcriptome, and 400 of them were further validated in a breast cancer cohort. Biological function analyses suggested that several pathways were involved in Cd-induced breast carcinogenesis, such as Wnt signaling, metabolism, and human papilloma virus (HPV) infection. TXNRD1 and CCT3 were further identified as the critical genes based on the degree of expression change, hazard ratio difference, and connectivity. The present study revealed that Cd epigenetically regulated several pathways involving in breast carcinogenesis, particularly the Wnt signaling and metabolic pathways, among which TXNRD1 and CCT3 might play critical roles. It was also suggested that Cd and HPV infection might jointly participate in breast tumorigenesis.

Extreme variation in lifetime cancer risk among tissues has been a riddle of cancer etiology. Considering that cancer risks were found to be contributed heavily by environmental factors, levels of environmental carcinogens, such as metal/metalloid in tissues, may be an explanation of the variation. We analyzed the correlations between metal/metalloid concentrations in different tissues and the lifetime cumulative cancer risks of the corresponding tissues using the data of National Health Standards and National Central Cancer Registry of China. Cadmium (Cd) and rubidium (Rb) were found to be correlated with the lifetime cancer risks in a positive linear relationship while a U-shaped relationship was observed for cesium (Cs) and tin (Sn). A positive linear trend between the mixture of metals/metalloids and lifetime cancer risks was observed and cadmium (Cd) may be the main driving element. Our results indicated that Cd-based metal/metalloid levels may be an explanation for the variation in lifetime cancer risk among tissues. Furthermore, the analytical strategy may in turn help identify environmental factors involved in cancer etiology.

Young and elderly breast cancer patients are more likely to have a poorer outcome than middle‐aged patients. The intrinsic molecular features for this disparity are unclear. We obtained data from the Cancer Genome Atlas (TCGA) on May 15, 2017 to test the potential mediation effects of the molecular features on the association between age and prognosis with a four‐step approach. The relative contributions of the molecular features (PAM50 subtype, risk stratification, DNAm age, and mutations in TP53, PIK3CA, MLL3, CDH1, GATA3, and MAP3K1) to age disparities in survival were estimated by Cox proportional hazard models with or without the features. Young patients were significantly more likely to have basal‐like subtype, GATA3 mutations, and younger DNA methylation (DNAm) age than middle‐aged patients (P