Calorie restriction outperforms bariatric surgery in a murine model of obesity and triple-negative breast cancer.

Obesity promotes triple-negative breast cancer (TNBC), and effective interventions are urgently needed to break the obesity-TNBC link. Epidemiologic studies indicate that bariatric surgery reduces TNBC risk, while evidence is limited or conflicted for weight loss via low-fat diet (LFD) or calorie restriction (CR). Using a murine model of obesity-driven TNBC, we compared the antitumor effects of vertical sleeve gastrectomy (VSG) with LFD, chronic CR, and intermittent CR.

Separate and combined effects of advanced age and obesity on mammary adipose inflammation, immunosuppression and tumor progression in mouse models of triple negative breast cancer.

Introduction: Advanced age and obesity are independent risk and progression factors for triple negative breast cancer (TNBC), which presents significant public health concerns for the aging population and its increasing burden of obesity. Due to parallels between advanced age- and obesityrelated biology, particularly adipose inflammation, we hypothesized that advanced age and obesity each accelerate mammary tumor growth through convergent, and likely interactive, mechanisms.

Methods: To test this hypothesis, we orthotopically transplanted murine syngeneic TNBC cells into the mammary glands of young normoweight control (7 months), young diet-induced obese (DIO), aged normoweight control (17 months), and aged DIO female C57BL/6J mice.

Reversing the Genomic, Epigenetic, and Triple-Negative Breast Cancer-Enhancing Effects of Obesity.

Unlabelled: The reversibility of the procancer effects of obesity was interrogated in formerly obese C57BL/6 mice that lost weight via a nonrestricted low-fat diet (LFD) or 3 distinct calorie-restricted (CR) regimens (low-fat CR, Mediterranean-style CR, or intermittent CR). These mice, along with continuously obese mice and lean control mice, were orthotopically injected with E0771 cells, a mouse model of triple-negative breast cancer. Tumor weight, systemic cytokines, and incidence of lung metastases were elevated in the continuously obese and nonrestricted LFD mice relative to the 3 CR groups.

Cumulative impact of multiple evidence based strategies on postnatal growth of extremely-low-birth-weight infants.

Background: Postnatal growth failure is common in very preterm infants and is associated with worse neurodevelopmental outcome.

Objective: To evaluate the cumulative impact of multiple evidence based strategies on the postnatal growth of extremely-low-birth-weight (ELBW) infants.

Methods: We conducted a prospective observational study.

The role of immune dysfunction in obesity-associated cancer risk, progression, and metastasis.

Obesity has been linked to an increased risk of and a worse prognosis for several types of cancer. A number of interrelated mediators contribute to obesity's pro-tumor effects, including chronic adipose inflammation and other perturbations of immune cell development and function. Here, we review studies examining the impact of obesity-induced immune dysfunction on cancer risk and progression.

Multi-omics Analysis Reveals Adipose-tumor Crosstalk in Patients with Colorectal Cancer.

Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte-colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumor-adjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer.

Impact of order entry alerts and modifications on doses of intravenous opioids dispensed during a national drug shortage.

Purpose: To address the intravenous (i.v.) opioid shortage, computer-based alerts and modifications were implemented over 2 phases beginning in August 2017 and February 2018, respectively.

A bacteriophage mimic of the bacterial nucleoid-associated protein Fis.

We report the identification and characterization of a bacteriophage λ-encoded protein, NinH. Sequence homology suggests similarity between NinH and Fis, a bacterial nucleoid-associated protein (NAP) involved in numerous DNA topology manipulations, including chromosome condensation, transcriptional regulation and phage site-specific recombination. We find that NinH functions as a homodimer and is able to bind and bend double-stranded DNA in vitro.

The flaxseed lignan secoisolariciresinol diglucoside decreases local inflammation, suppresses NFκB signaling, and inhibits mammary tumor growth.

Purpose: Exposure to the polyphenolic plant lignan secoisolariciresinol diglucoside (SDG) and its metabolite enterolactone (ENL) has been associated with reduced breast cancer progression, particularly for estrogen receptor alpha (ERα)-negative disease, and decreased preclinical mammary tumor growth. However, while preclinical studies have established that SDG and ENL affect measures of progression in models of triple-negative breast cancer (TNBC, a subset of ERα-negative disease), the molecular mechanisms underlying these effects remain unclear.

Methods: C57BL/6 mice were fed a control diet (control, 10% kcal from fat) or control diet + SDG (SDG, 100 mg/kg diet) for 8 weeks, then orthotopically injected with syngeneic E0771 mammary tumor cells (a model of TNBC); tumor growth was monitored for 3 weeks.

Leptin Signaling Mediates Obesity-Associated CSC Enrichment and EMT in Preclinical TNBC Models.

Obesity is associated with poor prognosis in triple-negative breast cancer (TNBC). Preclinical models of TNBC were used to test the hypothesis that increased leptin signaling drives obesity-associated TNBC development by promoting cancer stem cell (CSC) enrichment and/or epithelial-to-mesenchymal transition (EMT). MMTV-Wnt-1 transgenic mice, which develop spontaneous basal-like, triple-negative mammary tumors, received either a control diet (10% kcal from fat) or a diet-induced obesity regimen (DIO, 60% kcal from fat) for up to 42 weeks ( = 15/group).

Resveratrol inhibits obesity-associated adipose tissue dysfunction and tumor growth in a mouse model of postmenopausal claudin-low breast cancer.

Adipose tissue dysregulation, a hallmark of obesity, contributes to a chronic state of low-grade inflammation and is associated with increased risk and progression of several breast cancer subtypes, including claudin-low breast tumors. Unfortunately, mechanistic targets for breaking the links between obesity-associated adipose tissue dysfunction, inflammation, and claudin-low breast cancer growth have not been elucidated. Ovariectomized female C57BL/6 mice were randomized (n = 15/group) to receive a control diet, a diet-induced obesity (DIO) diet, or a DIO + resveratrol (0.

Translating Mechanism-Based Strategies to Break the Obesity-Cancer Link: A Narrative Review.

Prevalence of obesity, an established risk factor for many cancers, has increased dramatically over the past 50 years in the United States and across the globe. Relative to normoweight cancer patients, obese cancer patients often have poorer prognoses, resistance to chemotherapies, and are more likely to develop distant metastases. Recent progress on elucidating the mechanisms underlying the obesity-cancer connection suggests that obesity exerts pleomorphic effects on pathways related to tumor development and progression and, thus, there are multiple opportunities for primary prevention and treatment of obesity-related cancers.

Signals from the Adipose Microenvironment and the Obesity-Cancer Link-A Systematic Review.

Obesity and its associated metabolic dysregulation are established risk factors for many cancers. However, the biologic mechanisms underlying this relationship remain incompletely understood. Given the rising rates of both obesity and cancer worldwide, and the challenges for many people to lose excess adipose tissue, a systematic approach to identify potential molecular and metabolic targets is needed to develop effective mechanism-based strategies for the prevention and control of obesity-driven cancer.

Energy Balance Modulation Impacts Epigenetic Reprogramming, ERα and ERβ Expression, and Mammary Tumor Development in MMTV-neu Transgenic Mice.

The association between obesity and breast cancer risk and prognosis is well established in estrogen receptor (ER)-positive disease but less clear in HER2-positive disease. Here, we report preclinical evidence suggesting weight maintenance through calorie restriction (CR) may limit risk of HER2-positive breast cancer. In female MMTV-HER2/neu transgenic mice, we found that ERα and ERβ expression, mammary tumorigenesis, and survival are energy balance dependent in association with epigenetic reprogramming.

Reducing the burden of obesity-associated cancers with anti-inflammatory long-chain omega-3 polyunsaturated fatty acids.

Today's world population has an unprecedented risk of dying from the consequences of being overweight and obese. Chronic diseases such as cardiovascular disease, type 2 diabetes, and cancer are often accelerated because of excessive adiposity. Various biological mechanisms are implicated in the obesity-cancer link, particularly local and systemic inflammation as well as altered growth factor signaling pathways.

Obesity-Associated Alterations in Inflammation, Epigenetics, and Mammary Tumor Growth Persist in Formerly Obese Mice.

Using a murine model of basal-like breast cancer, we tested the hypothesis that chronic obesity, an established breast cancer risk and progression factor in women, induces mammary gland epigenetic reprogramming and increases mammary tumor growth. Moreover, we assessed whether the obesity-induced epigenetic and protumor effects are reversed by weight normalization. Ovariectomized female C57BL/6 mice were fed a control diet or diet-induced obesity (DIO) regimen for 17 weeks, resulting in a normal weight or obese phenotype, respectively.

Obesity Suppresses Estrogen Receptor Beta Expression in Breast Cancer Cells via a HER2-Mediated Pathway.

Obesity is associated with a worse breast cancer prognosis, while greater breast tumor estrogen receptor beta (ERβ) expression is correlated with improved therapy response and survival. The objective of this study was to determine the impact of obesity on breast cancer cell ERβ expression, which is currently unknown. We utilized an in vitro model of obesity in which breast cancer cells were exposed to patient serum pooled by body mass index category (obese (OB): ≥30 kg/m2; normal weight (N): 18.

Targeting the COX-2 Pathway to Improve Therapeutic Response in the Obese Breast Cancer Patient Population.

Multiple studies have demonstrated that obesity is associated with a worse outcome for all breast cancer subtypes and that obese breast cancer patients do not respond as well as normal weight patients to aromatase inhibitor treatment and chemotherapy. While a number of mechanisms have been proposed to explain this link, recent studies have provided evidence that elevated local cyclooxygenase-2 (COX-2) expression and the resulting increase in prostaglandin E2 (PGE2) production may play an important role. COX-2 upregulation in breast tumors is associated with a poor prognosis, a connection generally attributed to PGE2's direct effects on apoptosis and invasion as well as its stimulation of pre-adipocyte aromatase expression and subsequent estrogen production.

A weighty problem: metabolic perturbations and the obesity-cancer link.

Obesity is an established risk factor for several cancers, including breast, colon, endometrial, ovarian, gastric, pancreatic and liver, and is increasingly a public health concern. Obese cancer patients often have poorer prognoses, reduced response to standard treatments, and are more likely to develop metastatic disease than normo-weight individuals. Many of the pathologic features of obesity promote tumor growth, such as metabolic perturbations, hormonal and growth factor imbalances, and chronic inflammation.

Omega-3-Acid Ethyl Esters Block the Protumorigenic Effects of Obesity in Mouse Models of Postmenopausal Basal-like and Claudin-Low Breast Cancer.

Obesity induces chronic inflammation and is an established risk and progression factor for triple-negative breast cancers, including basal-like (BL) and claudin-low (CL) subtypes. We tested the effects of dietary supplementation with ethyl esters of the marine-derived anti-inflammatory omega-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA+DHA; Lovaza) on growth of murine BL and CL mammary tumors. Female ovariectomized C57BL/6 mice were fed a control diet or a diet-induced obesity (DIO) diet with or without EPA+DHA (0.

The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link.

Numerous epidemiological and pre-clinical studies have demonstrated that the insulin/insulin-like growth factor (IGF) system plays a key role in the development and progression of several types of cancer. Insulin/IGF signaling, in cooperation with chronic low-grade inflammation, is also an important contributor to the cancer-promoting effects of obesity. However, clinical trials for drugs targeting different components of this system have produced largely disappointing results, possibly due to the lack of predictive biomarker use and problems with the design of combination therapy regimens.

Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production.

Obesity is associated with a worse breast cancer prognosis, particularly in estrogen receptor alpha (ERα) positive, postmenopausal patients. We hypothesized that this is mediated in part by an elevation in breast cancer cell cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production that results in greater local pre-adipocyte aromatase expression. We utilized an in vitro model of the obese patient's tumor microenvironment in which cultured MCF-7 breast cancer cells and pre-adipocytes were exposed to pooled serum from obese (OB; BMI ≥ 30.