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Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO with the goal of collecting valuable data on the biologic effects of denosumab on gynecologic tissue. The study was terminated early due to the inability to accrue participants. Challenges which impacted the conduct of this study included a study design with highly selective eligibility criteria and requirements and the COVID-19 pandemic. It is critical to reflect on these issues to enhance the successful completion of future prevention studies in individuals with hereditary cancer syndromes.

Supplementary Figures and Tables

Percent change in E-cadherin expression after treatment.

Supplementary table showing demographic information and protein docing.

Influence of SH3GL2 overexpression in BCa cells.

Purpose: Pregnancy increases breast cancer risk for all women for at least 5 years after parturition. During weaning and involution, the breast microenvironment becomes tumor promotional. Exosomes provide cell–cell communication during physiologic processes such as lactation, but also in breast cancer. We determined whether molecules in milk exosomes from healthy lactating women modulate the development and progression of breast cancer.Experimental Design: Thirteen nursing women provided three (transitional, mature, and wean) milk samples. Exosomes were extracted and MCF7 and MCF10A breast cells labeled. The expression of six proteins linked to breast cancer was measured. On the basis of the findings, TGFβ2 concentration in exosome samples was measured, breast cells incubated with the exosomes and effect (epithelial–mesenchymal transition, EMT) on EMT-related proteins [E-cadherin, α-smooth muscle actin (α-SMA), filamentous (F)-actin and vimentin] measured.Results: Human milk exosomes entered benign and malignant breast cells. The greatest change in wean milk protein was in TGFβ2 (P = 0.01). Exosomes with a high (but not low) level of TGFβ2 led to EMT in both cancer and benign cells, based on (i) change in cell morphology, actin cytoskeleton, and loss of cell–cell junction structure and (ii) increased α-SMA and vimentin and decreased E-cadherin.Conclusions: TGFβ2 is significantly upregulated in breast milk exosomes during weaning/early involution. Breast milk exosomes containing high levels of TGFβ2 induce changes in both benign and malignant breast epithelial cells, consistent with the development and progression of breast cancer, suggesting a role for high TGFβ2-expressing breast milk exosomes in influencing breast cancer risk. Clin Cancer Res; 22(17); 4517–24. ©2016 AACR.

Tables show realtime PCR primers and compositions of diets. Figures show that n-3 EPA induce pro-tumor macrophage effects in the fish oil HFD-induced obese mouse models.

Legends for Supplementary Figures 1-6.

Purpose: The goal of this study was to understand the role of altered mitochondrial function in breast cancer progression and determine the potential of the molecular alteration signature in developing exosome-based biomarkers.Experimental Design: This study was designed to characterize the critical components regulating mitochondrial function in breast tumorigenesis. Experiments were conducted to assess the potential of these molecules for exosome-based biomarker development.Results: We observed a remarkable reduction in spontaneous metastases through the interplay in mitochondria by SH3GL2, vesicular endocytosis–associated protein and MFN2, an important regulator of mitochondrial fusion. Following its overexpression in breast cancer cells, SH3GL2 translocated to mitochondria and induced the production of superoxide and release of cytochrome C from mitochondria to the cytoplasm. These molecular changes were accompanied by decreased lung and liver metastases and primary tumor growth. SH3GL2 depletion reversed the above phenotypic and associated molecular changes in nontumorigenic and tumorigenic breast epithelial cells. Loss of SH3GL2 and MFN2 expression was evident in primary human breast cancer tissues and their positive lymph nodes, which was associated with disease progression. SH3GL2 and MFN2 expression was detected in sera exosomes of normal healthy women, but barely detectable in the majority of the women with breast cancer exhibiting SH3GL2 and MFN2 loss in their primary tumors.Conclusions: This study identified a new mitochondria reprogramming pathway influencing breast cancer progression through SH3GL2 and MFN2. These proteins were frequently lost in breast cancer, which was traceable in the circulating exosomes. Clin Cancer Res; 22(13); 3348–60. ©2016 AACR.

Obesity is associated with increased risk of many types of cancer and can be induced by various high-fat diets (HFD) from different fat sources. It remains unknown whether fatty acid composition in different HFD influences obesity-associated tumor development. Here we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated mammary tumor growth, consumption of the fish oil HFD uncoupled obesity from increased mammary tumor growth and exhibited a decrease in protumor macrophages. Compared with fatty acid (FA) components in both HFDs, n-3 FA rich in the fish oil HFD induced significant production of reactive oxygen species (ROS) and macrophage death. Moreover, A-FABP expression in the protumor macrophages facilitated intracellular transportation of n-3 FA and oxidation of mitochondrial FA. A-FABP deficiency diminished n-3 FA–mediated ROS production and macrophage death in vitro and in vivo. Together, our results demonstrate a novel mechanism by which n-3 FA induce ROS-mediated protumor macrophage death in an A-FABP–dependent manner.Significance:This study provides mechanistic insight into dietary supplementation with fish oil for breast cancer prevention and advances a new concept that not all HFDs leading to obesity are tumorigenic.

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The most recent American Dietary Guidelines (2020–2025) recommend shifting dietary fats from solid saturated fats to unsaturated oils. Dietary oils contain different compositions of unsaturated fatty acids (UFA). Oleic acid (OA) and linoleic acid (LA) are the most common UFA in dietary oils. How individual UFA in oils regulate immune cell function and cancer risk remains unclear. Here we demonstrated that high-fat diets (HFD) rich either in OA or LA induced a similar degree of murine obesity, but the LA-rich HFD specifically promoted mammary tumor growth. LA impaired antitumor T-cell responses by promoting naïve T-cell apoptosis and inhibiting TNFα production. While exogenous OA and LA were taken up by T cells with similar efficacy, only LA induced significant mitochondrial reactive oxygen species production and lipid peroxidation. Importantly, naïve T cells predominantly expressed epidermal fatty acid binding protein (E-FABP), which is central in facilitating LA mitochondrial transport and cardiolipin incorporation. Genetic depletion of E-FABP rescued LA-impaired T-cell responses and suppressed LA-rich HFD-associated mammary tumor growth. Collectively, these data suggest that dietary oils high in LA promote mammary tumors by inducing E-FABP–mediated T-cell dysfunction.Significance:These findings suggest that modulation of dietary oil composition and inhibition of E-FABP activity may represent novel strategies to enhance T-cell function in the prevention and treatment of obesity-associated cancers.

The most recent American Dietary Guidelines (2020–2025) recommend shifting dietary fats from solid saturated fats to unsaturated oils. Dietary oils contain different compositions of unsaturated fatty acids (UFA). Oleic acid (OA) and linoleic acid (LA) are the most common UFA in dietary oils. How individual UFA in oils regulate immune cell function and cancer risk remains unclear. Here we demonstrated that high-fat diets (HFD) rich either in OA or LA induced a similar degree of murine obesity, but the LA-rich HFD specifically promoted mammary tumor growth. LA impaired antitumor T-cell responses by promoting naïve T-cell apoptosis and inhibiting TNFα production. While exogenous OA and LA were taken up by T cells with similar efficacy, only LA induced significant mitochondrial reactive oxygen species production and lipid peroxidation. Importantly, naïve T cells predominantly expressed epidermal fatty acid binding protein (E-FABP), which is central in facilitating LA mitochondrial transport and cardiolipin incorporation. Genetic depletion of E-FABP rescued LA-impaired T-cell responses and suppressed LA-rich HFD-associated mammary tumor growth. Collectively, these data suggest that dietary oils high in LA promote mammary tumors by inducing E-FABP–mediated T-cell dysfunction. Significance: These findings suggest that modulation of dietary oil composition and inhibition of E-FABP activity may represent novel strategies to enhance T-cell function in the prevention and treatment of obesity-associated cancers.

A growing body of literature examines the potential benefits of a time-based diet strategy referred to as time-restricted eating (TRE). TRE, a type of intermittent fasting, restricts the time of eating to a window of 4-12 h/d but allows ad libitum intake during eating windows. Although TRE diets do not overtly attempt to reduce energy intake, preliminary evidence from small studies suggests that TRE can lead to concomitant reduction in total energy, improvements in metabolic health, and weight loss. Unique features of the TRE diet strategy may facilitate adherence and long-term weight loss maintenance. In this Perspective, we explore the potential multilevel (i.e., biological, behavioral, psychosocial, environmental) facilitators and barriers of TRE for long-term weight loss maintenance in comparison with the more commonly used diet strategy, caloric restriction (CR). Compared with CR, TRE may facilitate weight loss maintenance by counteracting physiological adaptations to weight loss (biological), allowing for usual dietary preferences to be maintained (behavioral), preserving executive functioning (psychosocial), and enabling individuals to withstand situational pressures to overeat (environmental). However, TRE may also pose unique barriers to weight loss maintenance, particularly for individuals with poor baseline diet quality, internal or social pressures to eat outside selected windows (e.g., grazers), and competing demands that interfere with the scheduling of eating. Future studies of TRE in free-living individuals should consider the multiple levels of influence impacting long-term adherence and weight loss maintenance. Ultimately, TRE could be one strategy in a toolkit of tailored diet strategies to support metabolic health and weight loss maintenance.

Metabolic syndrome consists of a constellation of clinical factors associated with an increased risk of cardiovascular disease, type 2 diabetes, and cancer. Preclinical studies demonstrate that restricting the time during a 24-hour period when an obese animal eats (time-restricted feeding) leads to metabolic benefits. These benefits, which may or may not be associated with weight loss, often lead to improvements in glucose tolerance and insulin sensitivity. Studies seeking to determine whether similar benefits result when humans restrict daily eating time (time-restricted eating) are less mature and less consistent in their findings. In this commentary, we outline some of the exciting preclinical findings, the challenges that preliminary studies in humans present, and efforts of the US National Institutes of Health and specifically the National Cancer Institute to address the role of time-restricted eating in cancer.

Obesity is associated with increased risk of many types of cancer and can be induced by various high-fat diets (HFD) from different fat sources. It remains unknown whether fatty acid composition in different HFD influences obesity-associated tumor development. Here we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated mammary tumor growth, consumption of the fish oil HFD uncoupled obesity from increased mammary tumor growth and exhibited a decrease in protumor macrophages. Compared with fatty acid (FA) components in both HFDs, n-3 FA rich in the fish oil HFD induced significant production of reactive oxygen species (ROS) and macrophage death. Moreover, A-FABP expression in the protumor macrophages facilitated intracellular transportation of n-3 FA and oxidation of mitochondrial FA. A-FABP deficiency diminished n-3 FA–mediated ROS production and macrophage death in vitro and in vivo. Together, our results demonstrate a novel mechanism by which n-3 FA induce ROS-mediated protumor macrophage death in an A-FABP–dependent manner. Significance: This study provides mechanistic insight into dietary supplementation with fish oil for breast cancer prevention and advances a new concept that not all HFDs leading to obesity are tumorigenic.

Introduction: Naturally occurring compounds play an essential role in the prevention and treatment of various cancers. There are more than 100 plant and animal based natural compounds currently in clinical use.Areas covered: 1) The importance of natural products combinations in the prevention and treatment of cancer, 2) the need to maximize efficacy while minimizing side effects when using natural product combinations, and 3) specifics related to plant and animal derived natural products, as well as agents derived from natural products. Therapies using natural compounds that have been investigated, their rationale, mechanism of action and findings are reviewed. When the data warrant it, combined interventions that appear to increase efficacy (compared with monotherapy) while minimizing toxicity have been highlighted. Pubmed was used to search for relevant publications.Expert opinion: Combination therapy with natural compounds has the potential to be more effective than single agent therapy. Similar to pharmacologic agents, the goal is to maximize efficacy while mimimizing potential side effects. There is an increasing research focus on the development of agents derived from natural products, with notable successes already achieved from the effort.

To evade immune surveillance, tumors develop a hostile microenvironment that inhibits anti-tumor immunity. Recent immunotherapy breakthroughs that target the reinvigoration of tumor-infiltrating T lymphocytes (TIL) have led to unprecedented success in treating some cancers that are resistant to conventional therapy, suggesting that T cells play a pivotal role in anti-tumor immunity. In the hostile tumor microenvironment (TME), activated T cells are known to mainly rely on aerobic glycolysis to facilitate their proliferation and anti-tumor function. However, TILs usually exhibit an exhausted phenotype and impaired anti-tumor activity due to the limited availability of key nutrients (e.g., glucose) in the TME. Given that different T cell subsets have unique metabolic pathways which determine their effector function, this review introduces our current understanding of T cell development, activation signals and metabolic pathways. Moreover, emerging evidence suggests that fatty acid binding protein 5 (FABP5) expression in T cells regulates T cell lipid metabolism and function. We highlight how FABP5 regulates fatty acid uptake and oxidation, thus shaping the survival and function of different T cell subsets in the TME.

Depilatory creams are widely used to remove unwanted body hair, but people with sensitive skin are subject to depilatory-induced skin burn/inflammation. It remains unknown what makes their skin more sensitive than others. In this study, we show that epidermal fatty acid‒binding protein (E-FABP) expressed in the skin plays a critical role in promoting depilatory-induced acute skin inflammation in mouse models. Although a depilatory cream removed hair by breaking down keratin disulfide bonds, it activated cytosolic phospholipase A2, leading to activation of the arachidonic acid/E-FABP/peroxisome proliferator-activated receptor β signaling pathway in keratinocytes. Specifically, peroxisome proliferator-activated receptor β activation induced downstream targets (e.g., cyclooxygenase 2) and chemokine (e.g., CXCL1) production, which systemically mobilized neutrophils and recruited them to localize in the skin for acute inflammatory responses. Importantly, E-FABP deletion by CRISPR-Cas9 reduced cytosolic phospholipase A2/peroxisome proliferator-activated receptor β activation in keratinocytes, and genetic deletion of E-FABP protected mice from depilatory cream-induced neutrophil recruitment and skin inflammation. Our findings suggest E-FABP as a molecular sensor for sensitive skin by triggering depilatory-induced, lipid-mediated skin inflammatory responses.

We address the dilemma faced by oncologists in administering preventative measures to “at risk” patients diagnosed with atypical and nonatypical hyperplasias due to lack of any molecular means of risk stratification and identifying high-risk subjects. Our study purpose is to investigate a four marker risk signature, MMP-1, CEACAM6, HYAL1, and HEC1, using 440 hyperplastic tissues for identifying high-risk subjects who will benefit from preventative therapies. We assayed the markers by IHC and combined their expression levels to obtain a composite value from 0–10, which we called a “Cancer Risk Score.” We demonstrate that the four marker-based risk scores predict subsequent cancer development with an accuracy of 91% and 86% for atypical and nonatypical subjects, respectively. We have established a correlation between risk scores and cancer rates by stratifying the samples into low risk (score ≤ 0.5); intermediate risk (score ≤ 5.4), and high risk (score >5.4) groups using Kaplan–Meier survival analysis. We have evaluated cancer rates at 5, 10, and 15 years. Our results show that the average cancer rates in the first 5 years among low- and intermediate-risk groups were 2% and 15%, respectively. Among high-risk group, the average cancer rates at 5 years were 73% and 34% for atypical and nonatypical subjects, respectively. The molecular risk stratification described here assesses a patient's tumor biology–based risk level as low, intermediate, or high and for making informed treatment decisions. The outcomes of our study in conjunction with the available prophylactic measures could prevent approximately 20%–25% of sporadic breast cancers.

Background: The underlying mechanisms that drive obesity-related breast cancer remain unclear. Adipocyte/macrophage fatty acid binding protein (A-FABP) is linked to obesity and breast cancer, while transforming growth factor (TGF)β appears to play a pleiotropic role in breast cancer, suppressing its development but promoting its progression. Whether the proteins work together to drive breast cancer progression is not known. We evaluated the expression of these two markers in matched serum from healthy women and women with breast cancer. Hypothesis: A-FABP and TGFβ drive breast cancer development and progression. Methods: Serum was collected under an institutional review board approved protocol. A-FABP was measured in serum collected from 275 women (92 with breast cancer and 183 without) and TGFβ from 245 matched women (92 with breast cancer and 153 without). A-FABP levels were measured using a human A-FABP4 ELISA kit while TGFβ was measured using human TGFβ ELISA kit. The Kruskal-Wallis test was used to determine if a difference in marker expression existed between women with and without breast cancer, as well as in women with early vs. more advanced breast cancer. Linear mixed effect models were used to examine the relationship between A-FABP and BMI, as well as between TGFβ and BMI, controlling for age, menopause status and a diagnosis of breast cancer. Results:A-FABP expression was higher in obese than lean postmenopausal women, both those with breast cancer (mean : 44.9 vs. 25.1 ng/mL, p=0.002) and without breast cancer (39.4 vs. 26.9 ng/mL, p=0.003). A-FABP expression was also higher in premenopausal obese vs. lean women with cancer (28.9 vs. 12.7 ng/mL, p=0.027), but not in premenopausal healthy women. A-FABP expression was higher in postmenopausal obese vs. lean women with early stage (0-2A) breast cancer (45.6 vs. 21.9 ng/mL, p=0.013) and was inversely associated with HER-2 expression, though being of borderline significance (p=0.060). This was most notable among triple negative vs. ER/PR negative HER2 positive breast cancers. Considering both early and advanced breast cancer, TGFβ expression trended higher in post- than in pre-menopausal obese women with breast cancer (138.9 vs. 68.7 pg/mL, p=0.061), however among premenopausal women with advanced (Stages 2B-3C) disease, TGFβ expression was 5 fold higher in lean than obese individuals (251.7 vs. 48.2 pg/mL, p=0.029) but trended higher in obese vs lean postmenopausal women. TGFβ and A-FABP were found to be significantly associated (ρ=0.14, p=0.024). Impact: Both A-FABP and TGFβ expression are associated with postmenopausal breast cancer among obese women, and their expression in matched samples is significantly associated.. TGFβ is associated with premenopausal advanced breast cancer in premenopausal women. TGFβ is known to induce epithelial mesenchymal transition and may play a role in pregnancy associated breast cancer. Further studies are needed to determine if A-FABP and TGFβ work together in postmenopausal breast cancer. Citation Format: Sauter E, Hao J, Yan X, Kong M, Li B. Expression of adipocyte fatty acid binding protein promotes obesity-associated mammary tumor growth [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-12-07.

Simple Summary Metabolic (bariatric) surgery (MBS) provides the greatest maximum and sustained weight loss among individuals who are morbidly obese. It is more effective than lifestyle interventions in improving or eliminating type 2 diabetes mellitus (T2DM) and in decreasing cardiovascular (CV) risk. Preclinical studies have been conducted to investigate the mechanisms by which MBS leads to the benefits in T2DM and CV risk. In this review, we describe the emerging evidence that MBS may also impact cancer risk and mortality, and whom may benefit most. We describe the long term involvement and commitment of the National Institutes of Health in obesity research in general and MBS in particular. We outline the need for additional research to understand the mechanism(s) by which MBS may influence cancer, since these mechanism(s) are currently unknown. Abstract Metabolic (bariatric) surgery (MBS) is recommended for individuals with a BMI > 40 kg/m2 or those with a BMI 35–40 kg/m2 who have one or more obesity related comorbidities. MBS leads to greater initial and sustained weight loss than nonsurgical weight loss approaches. MBS provides dramatic improvement in metabolic function, associated with a reduction in type 2 diabetes mellitus and cardiovascular risk. While the number of MBS procedures performed in the U.S. and worldwide continues to increase, they are still only performed on one percent of the affected population. MBS also appears to reduce the risk of certain obesity related cancers, although which cancers are favorably impacted vary by study, who benefits most is uncertain, and the mechanism(s) driving this risk reduction are mostly speculative. The goal of this manuscript is to highlight (1) emerging evidence that MBS influences cancer risk, and that the potential benefit appears to vary based on cancer, gender, surgical procedure, and likely other variables; (2) the role of the NIH in MBS research in T2DM and CV risk for many years, and more recently in cancer; and (3) the opportunity for research to understand the mechanism(s) by which MBS influences cancer. There is evidence that women benefit more from MBS than men, that MBS may actually increase the risk of colorectal cancer in both women and men, and there is speculation that the benefit in cancer risk reduction may vary according to which MBS procedure an individual undergoes. Herein, we review what is currently known, the historical role of government, especially the National Institutes of Health (NIH), in driving this research, and provide suggestions that we believe could lead to a better understanding of whether and how MBS impacts cancer risk, which cancers are impacted either favorably or unfavorably, the role of the NIH and other research agencies, and key questions to address that will help us to move the science forward.

Macrophages are almost everywhere in the body, where they serve pivotal functions in maintaining tissue homeostasis, remodeling, and immunoregulation. Macrophages are traditionally thought to differentiate from bone marrow-derived hematopoietic stem cells (HSCs). Emerging studies suggest that some tissue macrophages at steady state originate from embryonic precursors in the yolk sac or fetal liver and are maintained in situ by self-renewal, but bone marrow-derived monocytes can give rise to tissue macrophages in pathogenic settings, such as inflammatory injuries and cancer. Macrophages are popularly classified as Th1 cytokine (e.g. IFNγ)-activated M1 macrophages (the classical activation) or Th2 cytokine (e.g. IL-4)-activated M2 macrophages (the alternative activation). However, given the myriad arrays of stimuli macrophages may encounter from local environment, macrophages exhibit notorious heterogeneity in their phenotypes and functions. Determining the underlying metabolic pathways engaged during macrophage activation is critical for understanding macrophage phenotypic and functional adaptivity under different disease settings. Fatty acid binding proteins (FABPs) represent a family of evolutionarily conserved proteins facilitating lipid transport, metabolism and responses inside cells. More specifically, adipose-FABP (A-FABP) and epidermal-FABP (E-FABP) are highly expressed in macrophages and play a central role in integrating metabolic and inflammatory pathways. In this review we highlight how A-FABP and E-FABP are respectively upregulated in different subsets of activated macrophages and provide a unique perspective in defining macrophage phenotypic and functional heterogeneity through FABP-regulated lipid metabolic and inflammatory pathways.

Intraductal assessment of the breast holds the potential to provide useful information regarding breast cancer risk assessment, early diagnosis, and/or response to therapy. Intraductal assessment can be through imaging (ductography), direct visualization (mammary ductoscopy), or evaluation of the intraductal fluid collected. The most common nonradiologic approaches to intraductal assessment that provide intraductal fluid for evaluation include breast nipple aspiration fluid (NAF), spontaneous nipple discharge (SND), mammary ductoscopy, and ductal lavage. The first two approaches are entirely noninvasive while the latter are considered minimally invasive. Nipple aspiration is performed both on women with and without evidence of possible disease in the breast. On the other hand, unilateral SND suggests the presence of a lesion in the incident breast, while bilateral SND is most often physiologic. The focus of the report by Patuleia and colleagues is on challenges, lessons learned, and recommended solutions in the identification of women with increased breast cancer risk who are more likely to develop in situ or invasive breast cancer based on sequential collection and subsequent analysis of biofluids (NAF and serum). The lessons learned that are discussed can also be applied to other types of biofluid studies for cancer early detection and response to treatment. See related article by Patuleia et al., p. 441

Fatty acid binding proteins (FABPs) serve as intracellular chaperones for fatty acids and other hydrophobic ligands inside cells. Recent studies have demonstrated new functions of individual members of the FABP family. This Snapshot describes the overall functions of FABPs in health and disease and highlights emerging roles of adipose FABP (A-FABP) and epidermal FABP (E-FABP) in the fields of obesity, chronic inflammation, and cancer development. To view this SnapShot, open or download the PDF.

Obesity is known to increase breast cancer incidence and mortality, but the underlying mechanisms remain unsolved. Recent studies demonstrate that adipose fatty acid binding protein (FABP4) promotes obesity-associated breast cancer development, thus suggesting FABP4 as a novel player linking obesity and breast cancer risk.

Obesity is associated with elevated levels of free fatty acids (FAs) and proinflammatory CD11c+ macrophages. However, whether and how free FAs contribute to CD11c+ macrophage differentiation and proinflammatory functions remain unclear. Here we report that dietary saturated FAs, but not unsaturated FAs, promoted the differentiation and function of CD11c+ macrophages. Specifically, we demonstrated that stearic acid (SA) significantly induced CD11c expression in monocytes through activation of the nuclear retinoid acid receptor. More importantly, cytosolic expression of epidermal FA binding protein (E-FABP) in monocytes/macrophages was shown to be critical to the mediation of the SA-induced effect. Depletion of E-FABP not only inhibited SA-induced CD11c upregulation in macrophages in vitro but also abrogated high-saturated-fat diet–induced skin lesions in obese mouse models in vivo. Altogether, our data demonstrate a novel mechanism by which saturated FAs promote obesity-associated inflammation through inducing E-FABP/retinoid acid receptor–mediated differentiation of CD11c+ macrophages.

This abstract was withdrawn by the authors.

Exosomes are the smallest of the extracellular vesicles (EVs). They have been detected in a variety of body fluids, including serum and plasma. Exosomes from tumor cells that are found in the circulation (and elsewhere) are enriched in certain intracellular components, including miRNAs. While many small studies document the association of miRNAs, DNA, protein or lipid alterations within exosomes with the presence of a given type of cancer, few if any of these findings have been independently validated. Indeed, there are many gaps in our knowledge of the role of extracellular RNA, DNA, proteins or lipids in cancer detection, prognosis or therapy. Some of the important questions which need to be addressed for a given cancer type include assessing which: (I) body fluid(s) to study; (II) molecular components within a given body fluid to study (RNA, DNA, proteins or lipids contained within and/or outside of EVs); and (III) specific markers within the body fluid fraction provide the most information regarding diagnosis, prognosis, and/or treatment of a given cancer. The most common body fluid analyzed to evaluate the role of exosomes in cancer is blood. Herein we review published findings related to studies that have analyzed exosomes obtained from blood or its components serum or plasma. We also review resources that are available to assist the clinician and scientist wishing to learn more about exosomes. Vesiculopedia and Exocarta are websites dedicated to gathering molecular information on EVs (all sizes) and exosomes, respectively. They contain information on EV content by molecular type (DNA, RNA, protein, lipid) and species from which the EV study originated. The International Society of Extracellular Vesicles and the Journal of Extracellular Vesicles are dedicated to advancing knowledge of EVs. The National Institutes of Health has funding 30 research grants which seek to increase our understanding of extracellular RNA, including that contained within EVs.

A primary tumor can spread locally through direct extension, regionally through lymphatic vessels, and distantly through lymphatic and blood vessels. The lymphatic and circulatory systems are interconnected at sites such as the thoracic and right lymphatic ducts, where they empty into the left and right subclavian veins, respectively. In this article we review how normal and tumor exosomes influence the lymph system, with special emphasis on tumor related exosomes.

Background/Aim: We reported that vitamin D3 increased transforming growth factor (TGF)β2 and decreased prostaglandin (PG)E2 in the breast of normal-risk women, suggesting a protective effect. We determined if the findings held for higher risk women. Patients and Methods: Seventy-eight women received daily for one month/menstrual cycle: placebo, 400 international units (IU) vitamin D3, 2,000 IU vitamin D3 or 2,000 IU vitamin D3/400 mg celecoxib. Nipple aspirate fluid (NAF) and/or serum were analyzed for PGE2, TGFβ1,-2, vitaminD binding protein (DBP) 25(OH)D; and plasma for celecoxib. Results: 25(OH)D increased (p

Oral cancer is the sixth most common cause of death from cancer with an estimated 400,000 deaths worldwide and a low (50%) 5-year survival rate. The most common form of oral cancer is oral squamous cell carcinoma (OSCC). OSCC is highly inflammatory and invasive, and the degree of inflammation correlates with tumor aggressiveness. The G protein-coupled receptor protease-activated receptor-2 (PAR-2) plays a key role in inflammation. PAR-2 is activated via proteolytic cleavage by trypsin-like serine proteases, including kallikrein-5 (KLK5), or by treatment with activating peptides. PAR-2 activation induces G protein-α-mediated signaling, mobilizing intracellular calcium and Nf-κB signaling, leading to the increased expression of pro-inflammatory mRNAs. Little is known, however, about PAR-2 regulation of inflammation-related microRNAs. Here, we assess PAR-2 expression and function in OSCC cell lines and tissues. Stimulation of PAR-2 activates Nf-κB signaling, resulting in RelA nuclear translocation and enhanced expression of pro-inflammatory mRNAs. Concomitantly, suppression of the anti-inflammatory tumor suppressor microRNAs let-7d, miR-23b, and miR-200c was observed following PAR-2 stimulation. Analysis of orthotopic oral tumors generated by cells with reduced KLK5 expression showed smaller, less aggressive lesions with reduced inflammatory infiltrate relative to tumors generated by KLK5-expressing control cells. Together, these data support a model wherein KLK5-mediated PAR-2 activation regulates the expression of inflammation-associated mRNAs and microRNAs, thereby modulating progression of oral tumors.

Women diagnosed with pregnancy-associated breast cancer postpartum have a worse prognosis, stage for stage, than other women with breast cancer. The time of breast involution is tumor promotional. The extracellular matrix protein tenascin-C is upregulated during involution in animal models and promotes breast cancer progression. It interacts with transforming growth factor (TGF)β, which also is involved in breast involution and breast cancer progression. Little is known about the expression of tenascin-C during human breast involution, nor its relationship to TGFβ. The purpose of this study was to investigate the expression of tenascin-C throughout lactation, as well as its relationship to TGFβ1 and TGFβ2.Three milk samples from 25 lactating women (transitional, whole, and wean) were collected, separated into components (cells, fat, and skim), and the skim fraction analyzed for total protein, tenascin-C, TGFβ1, and TGFβ2. Tenascin-C, TGFβ1, and TGFβ2 were detectable in all milk samples.Highest tenascin-C levels on average were found in whole milk, whereas highest mean TGFβ1 and TGFβ2 levels were in wean milk. Wean samples on average had higher levels of both TGFβ1 (26%) and TGFβ2 (500%) than matched transitional milk samples. Tenascin-C levels in wean milk were associated with nursing length (p = 0.048). Combining all three milk collection time points, tenascin-C exhibited a weak inverse correlation with TGFβ1 and TGFβ2 (p0.1). The inverse correlation at the wean time point was stronger for TGFβ2 than -1 (-0.37 versus -0.25). Tenascin-C, a protein known to promote breast cancer progression, is expressed throughout lactation.The inverse correlation with TGFβ2 in wean milk suggests a possible interaction during breast involution, which should be further investigated.

Background: We previously reported that postmenopausal obese women exhibit increased levels of circulating adipocyte fatty acid binding protein (A-FABP), which is associated with breast cancer (BC) development. In postmenopause, increased estrogen levels are associated with increased BC risk. Hypothesis: Estrogens (estrone: E1, estradiol: E2 and estriol: E3) are associated with A-FABP in the setting of obesity and obesity-related BC development. Methods: Immunoassays for E1, E2, E3, and A-FABP were performed using serum samples from women with and without BC. Results: Statistical analysis was conducted using the Mann-Whitney test and multiple linear regression models. Considering all subjects, E1 and E2 but not E3 levels were significantly higher in pre- than in postmenopause among both non-obese and obese individuals (p Impact: 1) A-FABP expression is increased in postmenopausal obese women with and without BC; 2) E1 and E2 expression is higher in pre- than postmenopausal women, regardless of BMI; 3) E1 and E3 levels are higher in lean than obese individuals, regardless of menopausal status; 4) the influence of obesity on E1, E2 and E3 expression in postmenopause is lost in women with BC, 5) E3 is increased in obese vs. non-obese women with BC, and 6) A-FABP and estrogens are independently involved in the development of BC. Citation Format: Bing Li, Jiaqing Hao, Xiaofang Yan, Maiying Kong, Edward Sauter. A-FABP and estrogens are independently involved in the development of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4363.

Mitochondria (mt) encoded respiratory complex-I (RCI) mutations and their pathogenicity remain largely unknown in prostate cancer (PCa). Little is known about the role of mtDNA loss on mt integrity in PCa. We determined mtDNA mutation in human and mice PCa and assessed the impact of mtDNA depletion on mt integrity. We also examined whether the circulating exosomes from PCa patients are transported to mt and carry mtDNA or mt proteins. We have employed next generation sequencing of the whole mt genome in human and Hi-myc PCa. The impact of mtDNA depletion on mt integrity, presence of mtDNA, and protein in sera exosomes was determined. A co-culture of human PCa cells and the circulating exosomes followed by confocal imaging determined co-localization of exosomes and mt. We observed frequent RCI mutations in human and Hi-myc PCa which disrupted corresponding complex protein expression. Depletion of mtDNA in PCa cells influenced mt integrity, increased expression of MFN1, MFN2, PINK1, and decreased expression of MT-TFA. Increased mt fusion and expression of PINK1 and DNM1L were also evident in the Hi-myc tumors. RCI-mtDNA, MFN2, and IMMT proteins were detected in the circulating exosomes of men with benign prostate hyperplasia (BPH) and progressive PCa. Circulating exosomes and mt co-localized in PCa cells. Our study identified new pathogenic RCI mutations in PCa and defined the impact of mtDNA loss on mt integrity. Presence of mtDNA and mt proteins in the circulating exosomes implicated their usefulness for biomarker development.

New onset diabetes and concurrent weight loss often occur several months before the clinical presentation of pancreatic cancer (PC).