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Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The emergence of whole-genome annotation approaches is paving the way for the comprehensive annotation of the human genome across diverse cell and tissue types exposed to various environmental conditions. This has already unmasked the positions of thousands of functional cis-regulatory elements integral to transcriptional regulation, such as enhancers, promoters, and anchors of chromatin interactions that populate the noncoding genome. Recent studies have shown that cis-regulatory elements are commonly the targets of genetic and epigenetic alterations associated with aberrant gene expression in cancer. Here, we review these findings to showcase the contribution of the noncoding genome and its alteration in the development and progression of cancer. We also highlight the opportunities to translate the biological characterization of genetic and epigenetic alterations in the noncoding cancer genome into novel approaches to treat or monitor disease., Significance: The majority of genetic and epigenetic alterations accumulate in the noncoding genome throughout oncogenesis. Discriminating driver from passenger events is a challenge that holds great promise to improve our understanding of the etiology of different cancer types. Advancing our understanding of the noncoding cancer genome may thus identify new therapeutic opportunities and accelerate our capacity to find improved biomarkers to monitor various stages of cancer development. Cancer Discov; 6(11); 1215-29. ©2016 AACR., Competing Interests: of Potential Conflicts of Interest No potential conflicts of interest to disclose., (©2016 American Association for Cancer Research.)

Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk-associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.

Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention., (Copyright © 2015 Elsevier Inc. All rights reserved.)

It is well known that protein tyrosine phosphatases (PTPs) that become oxidized due to exposure to reactive oxygen species (ROS) undergo a conformational change and are inactivated. However, whether PTPs can actively regulate ROS levels in order to prevent PTP inhibition has yet to be investigated. Here, we demonstrate that PTP non-receptor type 12 (PTPN12) protects cells against aberrant ROS accumulation and death induced by oxidative stress. Murine embryonic fibroblasts (MEFs) deficient in PTPN12 underwent increased ROS-induced apoptosis under conditions of antioxidant depletion. Cells lacking PTPN12 also showed defective activation of FOXO1/3a, transcription factors required for the upregulation of several antioxidant genes. PTPN12-mediated regulation of ROS appeared to be mediated by phosphoinositide-dependent kinase-1 (PDK1), which was hyperstimulated in the absence of PTPN12. As tight regulation of ROS to sustain survival is a key feature of cancer cells, we examined PTPN12 levels in tumors from a cohort of breast cancer patients. Patients whose tumors showed high levels of PTPN12 transcripts had a significantly poorer prognosis. Analysis of tissues from patients with various breast cancer subtypes revealed that more triple-negative breast cancers, the most aggressive breast cancer subtype, showed high PTPN12 expression than any other subtype. Furthermore, both human breast cancer cells and mouse mammary epithelial tumor cells engineered to lack PTPN12 exhibited reduced tumorigenic and metastatic potential in vivo that correlated with their elevated ROS levels. The involvement of PTPN12 in the antioxidant response of breast cancer cells suggests that PTPN12 may represent a novel therapeutic target for this disease.

This is an analysis of changes in menstrual cycle length and regularity occurring for a group of 211 women who had discontinued use of oral contraceptives. The analysis is based on prospectively recorded histories from the Menstruation and Reproduction History Program. Post-pill menstrual cycle length and regularity are compared with pre-pill averages. In the first post-pill cycle, there was an average increase of 6 days in cycle length. In subsequent cycles, however, cycle length and regularity were comparable to pre-pill norms in most cases.

Using a data set of women who longitudinally recorded menstrual and reproductive events, we examined menstrual cycle characteristics in relationship to early and late menarche, early and late menopause, and deferred parity, three variables epidemiologically related to breast cancer incidence. Women with late onset of menarche had longer and more variable cycles in the 10 years after menarche than did those with early onset. Women with late onset of menopause had longer and more variable cycles in the premenopausal interval than did those with early onset. Cumulative fertility in women after marriage did not differ according to cycle length and variance. Late menopause may be a breast cancer risk factor due to relative estrogen excess and progesterone lack as reflected in longer, more varied cycle patterns. Observed cycle differences between women with early and late menarche await further study of the endocrine physiology of the menstrual cycle in those groups.

The empirical percent probability that natural menopause has occurred after first presentation of amenorrhea of various durations in women greater than or equal to 45 years of age has been calculated using data from a cohort of subjects who prospectively recorded menstrual flow and related gynecologic events. The probability that menopause has occurred increases with the amenorrheal interval (duration), and for a given interval, the probability increases with age. After 180 days of amenorrhea, 45% to 72% of subjects were menopausal; after 360 days, 90%. These data may offer assistance in advising patients on the probability of menopause and the continuance of contraceptive practices, and in considering whether late genital bleeding after amenorrhea represents a physiologic or pathologic process.

The phase of menstrual life in which transition occurs from relatively regular cycles to the termination defined as menopause is studied for several hundred women who have kept accurate records of their menstrual flows. Age at both natural and oestrogenic menopause, age upon entry into the menopausal transition, and duration of that transition are analysed quantitatively. Detection of entry into the pre-menopausal phase is discussed. A complication of reactions to climacteric discomforts as recorded voluntarily by the study participants is presented.

Menstrual cycle lengths prior to and after oral contraceptive use were prospectively recorded for 245 women. In this preliminary study, a difference in the distributions in the pre- and post-pill cycle lengths was observed. An increase of 5 days in the medial cycle length occurred after oral contraceptive use had been discontinued. Although there was an approximately twofold relative risk of amenorrhea of 90 days' duration or more after discontinuing pill use, the differences in the rates of amenorrhea between the pre-pill and post-pill cycles were not statistically significant.

A prospective study of menstrual cycles and reproductive outcomes has been in progress since 1935. Data from this study are used to describe the risk of spontaneous abortion in two time periods 26 years apart. Out of the total of 3889 women who have enrolled in this study, two cohorts of women are selected for analysis: cohort one consists of 2070 university students who entered the study in 1935-1944, and cohort two consists of 1375 students a generation later, 1961-1970. Cohort one has contributed 2408 pregnancies, and cohort two, 1493 pregnancies. Overall spontaneous abortion risk for the two cohorts is 16.9% and 13.1%, respectively. However age-specific risks of spontaneous abortion do not differ for the two groups, nor is there a difference in the gestational duration of spontaneously aborted pregnancies.