There is emerging evidence that the balance between estrogen receptor-α (ERα) and androgen receptor (AR) signaling is a critical determinant of growth in the normal and malignant breast. In this study, we assessed AR status in a cohort of 215 invasive ductal breast carcinomas. AR and ERα were coexpressed in the majority (80-90%) of breast tumor cells. Kaplan-Meier product limit analysis and multivariate Cox regression showed that AR is an independent prognostic factor in ERα-positive disease, with a low level of AR (less than median of 75% positive cells) conferring a 4.6-fold increased risk of cancer-related death (P = 0.002). Consistent with a role for AR in breast cancer outcome, AR potently inhibited ERα transactivation activity and 17β-estradiol–stimulated growth of breast cancer cells. Transfection of MDA-MB-231 breast cancer cells with either functionally impaired AR variants or the DNA-binding domain of the AR indicated that the latter is both necessary and sufficient for inhibition of ERα signaling. Consistent with molecular modeling, electrophoretic mobility shift assays showed binding of the AR to an estrogen-responsive element (ERE). Evidence for a functional interaction of the AR with an ERE in vivo was provided by chromatin immunoprecipitation data, revealing recruitment of the AR to the progesterone receptor promoter in T-47D breast cancer cells. We conclude that, by binding to a subset of EREs, the AR can prevent activation of target genes that mediate the stimulatory effects of 17β-estradiol on breast cancer cells.

Androgen receptor inhibits estrogen receptor-A activity and is prognostic in breast cancer

The incidence of early-onset colorectal cancer (CRC), which occurs in individuals <50 years of age, has been increasing worldwide and particularly in high-income countries. The reasons for this increase remain unknown but plausible hypotheses include greater exposure to potential risk factors, such as a Western-style diet, obesity, physical inactivity and antibiotic use, especially during the early prenatal to adolescent periods of life. These exposures can not only cause genetic and epigenetic alterations in colorectal epithelial cells but also affect the gut microbiota and host immunity. Early-onset CRCs have differential clinical, pathological and molecular features compared with later-onset CRCs. Certain existing resources can be utilized to elucidate the aetiology of early-onset CRC and inform the development of effective prevention, early detection and therapeutic strategies; however, additional life-course cohort studies spanning childhood and young adulthood, integrated with prospective biospecimen collections, omics biomarker analyses and a molecular pathological epidemiology approach, are needed to better understand and manage this disease entity. In this Perspective, we summarize our current understanding of early-onset CRC and discuss how we should strategize future research to improve its prevention and clinical management.

Rising incidence of early-onset colorectal cancer - a call to action.

The implication of long non-coding RNAs in the diagnosis, pathogenesis and drug resistance of pancreatic ductal adenocarcinoma and their possible therapeutic potential.

LncRNAs in cancer: Regulatory and therapeutic implications.

Pancreatic cancer (PC) remains one of the most aggressive cancers worldwide. However, genetic factors underlying PC susceptibility remain largely unclear. Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) acts as an oncogene and its genetic variation has been linked to many cancers. However, the associations between genetic variants in HOTAIR gene and PC risk has not yet been reported. A two-stage, case–control study was conducted to investigate the associations between HOTAIR SNPs and the PC risk. Dual luciferase reporter assay and real-time -PCR (RT-PCR) was conducted to evaluate the potential regulatory function of HOTAIR rs4759314 and rs200349340. We found the minor alleles of rs4759314 (OR = 1.76; 95 CI 1.37–2.25; P = 0.001) and rs200349340 (OR = 1.32; 95 CI 1.12–1.56; P = 0.001) were significantly associated with PC susceptibility. In functional experiments, we found subjects carrying the minor alleles of rs4759314 and rs200349340 had significantly higher HOTAIR RNA levels (mean ± SD) than those carrying the major alleles in PC tissues. For rs4759314, cells transfected with rs4759314 -G allele construct showed higher relative luciferase activity; while for rs200349340, cells transfected with rs200349340 -G allele construct showed more sensitive change of the relative luciferase activity. Our studies revealed that functional SNP rs4759314 and rs200349340 of HOTAIR had strong associations with PC susceptibility. These findings elucidate that functional genetic variants influencing lncRNA expression may explain a portion of PC genetic basis.

/pdf/functional-polymorphisms-in-lncrna-hotair-contribute-to-4hfj97mvj2.pdf

Functional polymorphisms in LncRNA HOTAIR contribute to susceptibility of pancreatic cancer

Fusobacterium nucleatum, the communication with colorectal cancer.

Pancreatic cancer (PC) is one of the leading causes of cancer-related deaths worldwide. Due to the shortage of effective biomarkers for predicting survival and diagnosing PC, the underlying mechanism is still intensively investigated but poorly understood. Long noncoding RNAs (lncRNAs) provide biological functional diversity and complexity in protein regulatory networks. Scientific studies have revealed the emerging functions and regulatory roles of lncRNAs in PC behaviors. It is worth noting that some in-depth studies have revealed that lncRNAs are significantly associated with the initiation and progression of PC. As lncRNAs have good properties for both diagnostic and prognostic prediction due to their translation potential, we herein address the current understanding of the multifaceted roles of lncRNAs as regulators in the molecular mechanism of PC. We also discuss the possibility of using lncRNAs as survival biomarkers and their contributions to the development of targeted therapies based on the literature. The present review, based on what we know about current research findings, may help us better understand the roles of lncRNAs in PC.

/pdf/the-multifaceted-roles-of-long-noncoding-rnas-in-pancreatic-2esjdnatid.pdf

The multifaceted roles of long noncoding RNAs in pancreatic cancer: an update on what we know

The androgen receptor (AR, NR3C4) is believed to participate in the development of breast cancer, but its molecular mechanism and role in prognosis is still controversial and opaque. This study aimed to explore the expression, associations with clinicopathologic features and underlying molecular mechanisms of AR in breast cancer. The present study investigated invasive breast carcinoma through comprehensive bioinformatics. The expression and mutation rate of AR in breast cancer was obtained from the TCGA database. Training survival prediction analysis was applied to the data extracted from the KM plotter database. The prediction of the survival cohort was validated using the bcGenExMiner database in breast cancer molecular subgroups. Represented immunohistochemical images of AR and its related expression with the molecular subtype status were generated. The underlying molecular mechanism for AR in breast cancer was analyzed with the GEO dataset and Gene Ontology. A protein-to-protein interaction network and core pathways were constructed to show the protein functions with AR. Our results show that AR expression was significantly higher in cancerous tissue than in normal breast tissue and differentially expressed in the clinical stages. AR would also generally be considered as a favorable prognostic biomarker when including the major molecular subtypes of breast cancer. AR IHC staining could be easily used in clinical applications. The major molecular functions for AR were regulating the cell cycle checkpoints and chromatin remodeling. Our investigation showed that AR expression level could be used as a favorable and independent prognostic prediction factor for the disease-free survival time in breast cancer, especially for the ER-positive subgroup. However, AR was not a sensitive prognostic biomarker for the prediction of overall survival time or for the PR and TBC subgroups. In terms of the underlying molecular mechanism, AR may mainly participate in the cell cycle checkpoints related to the G1/S transition of the mitotic cell cycle to control the subdivision of the epithelial terminal unit and chromatin remodeling in breast cancer.

Rui Huang

Papers

Fusobacterium nucleatum, the communication with colorectal cancer.

The multifaceted roles of long noncoding RNAs in pancreatic cancer: an update on what we know

Diagnostic and prognostic role of NR3C4 in breast cancer through a genomic network understanding.