Benzo[a]pyrene exposure prevents high fat diet-induced obesity in the 4T1 model of mammary carcinoma.

Tumor metastasis is the main cause of death in triple-negative breast cancer (TNBC) patients. TNBC is the most aggressive subtype of breast cancer lacking the expression of estrogen, progesterone, and human epidermal growth factor 2 receptors, thereby rendering it insensitive to targeted therapies. It has been well-established that excess adiposity contributes to the progression of TNBC; however, due to the aggressive nature of this breast cancer subtype, it is imperative to determine how multiple factors can contribute to progression.

Non-Toxicological Role of Aryl Hydrocarbon Receptor in Obesity-Associated Multiple Myeloma Cell Growth and Survival.

Obesity is not only a risk factor for multiple myeloma (MM) incidence, but it is also associated with an increased risk of progression from myeloma precursors-monoclonal gammopathy of undetermined significance-and smoldering myeloma. Adipocytes in the bone marrow (BMAs) microenvironment have been shown to facilitate MM cell growth via secreted factors, but the nature of these secreted factors and their mechanism of action have not been fully elucidated. The elevated expression of aryl hydrocarbon receptor (AhR) is associated with a variety of different cancers, including MM; however, the role of AhR activity in obesity-associated MM cell growth and survival has not been explored.

The impact of poor metabolic health on aggressive breast cancer: adipose tissue and tumor metabolism.

Obesity and type 2 diabetes are chronic metabolic diseases that impact tens to hundreds of millions of adults, especially in developed countries. Each condition is associated with an elevated risk of breast cancer and with a poor prognosis after treatment. The mechanisms connecting poor metabolic health to breast cancer are numerous and include hyperinsulinemia, inflammation, excess nutrient availability, and adipose tissue dysfunction.

Adipocyte-derived kynurenine stimulates malignant transformation of mammary epithelial cells through the aryl hydrocarbon receptor.

Anti-hormone therapies are not efficacious for reducing the incidence of triple negative breast cancer (TNBC), which lacks both estrogen and progesterone receptors. While the etiology of this aggressive breast cancer subtype is unclear, visceral obesity is a strong risk factor for both pre- and post-menopausal cases. The mechanism by which excessive deposition of visceral adipose tissue (VAT) promotes the malignant transformation of hormone receptor-negative mammary epithelial cells is currently unknown.

Obesity alters the mouse endometrial transcriptome in a cell context-dependent manner.

Obesity impacts fertility and is positively correlated with endometrial hyperplasia and endometrial cancer occurrence. Endometrial epithelia often harbor disease driver-mutations, while endometrial stroma are highly regulative of neighboring epithelia. Here, we sought to determine distinct transcriptome changes occurring in individual cell types in the obese mouse uterus.

Expedient Synthesis of a Library of Heparan Sulfate-Like "Head-to-Tail" Linked Multimers for Structure and Activity Relationship Studies.

Heparan sulfate (HS) plays important roles in many biological processes. The inherent complexity of naturally existing HS has severely hindered the thorough understanding of their structure-activity relationship. To facilitate biological studies, a new strategy has been developed to synthesize a HS-like pseudo-hexasaccharide library, where HS disaccharides were linked in a "head-to-tail" fashion from the reducing end of a disaccharide module to the non-reducing end of a neighboring module.

Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma.

Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers.

The Use of Human Serum Samples to Study Malignant Transformation: A Pilot Study.

Obesity and excess adiposity account for approximately 20% of all cancer cases; however, biomarkers of risk remain to be elucidated. While fibroblast growth factor-2 (FGF2) is emerging as an attractive candidate biomarker for visceral adipose tissue mass, the role of circulating FGF2 in malignant transformation remains unknown. Moreover, functional assays for biomarker discovery are limited.

The Tumor Promotional Role of Adipocytes in the Breast Cancer Microenvironment and Macroenvironment.

The role of the adipocyte in the tumor microenvironment has received significant attention as a critical mediator of the obesity-cancer relationship. Current estimates indicate that 650 million adults have obesity, and thirteen cancers, including breast cancer, are estimated to be associated with obesity. Even in people with a normal body mass index, adipocytes are key players in breast cancer progression because of the proximity of tumors to mammary adipose tissue.

The Relationship between Leptin, the Leptin Receptor and FGFR1 in Primary Human Breast Tumors.

Obesity is associated with increased breast cancer risk and poorer cancer outcomes; however, the precise etiology of these observations has not been fully identified. Our previous research suggests that adipose tissue-derived fibroblast growth factor-2 (FGF2) promotes the malignant transformation of epithelial cells through the activation of fibroblast growth factor receptor-1 (FGFR1). FGF2 is increased in the context of obesity, and increased sera levels have been associated with endocrine-resistant breast cancer.

Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay.

Obesity is associated with ~40% of cancer diagnoses but there are currently no effective preventive strategies, illustrating a need for chemoprevention. We previously demonstrated that fibroblast growth factor 2 (FGF2) from adipose tissue stimulates malignant transformation, as measured by growth in soft agar, the gold-standard in vitro transformation assay. Because the soft agar assay is unsuitable for high throughput screens (HTS), we developed a novel method using 3D growth in ultra-low attachment conditions as an alternative to growth in agar to discover compounds that inhibit transformation.

Photoimmunology: how ultraviolet radiation affects the immune system.

Ultraviolet (UV) radiation is a ubiquitous component of the environment that has important effects on a wide range of cell functions. Short-wavelength UVB radiation induces sunburn and is a potent immunomodulator, yet longer-wavelength, lower-energy UVA radiation also has effects on mammalian immunity. This Review discusses current knowledge regarding the mechanisms by which UV radiation can modify innate and adaptive immune responses and how this immunomodulatory capacity can be both beneficial in the case of inflammatory and autoimmune diseases, and detrimental in the case of skin cancer and the response to several infectious agents.

Lipectomizing Mice for Applications in Metabolism.

The obesity epidemic is a critical public health problem closely associated with the development of metabolic disease. In obesity there is excess white adipose tissue, a dynamic tissue that has many biological functions. Specifically visceral adipose tissue (VAT) is an active endocrine organ producing hormones that control systemic metabolism.

A role for FGF2 in visceral adiposity-associated mammary epithelial transformation.

Obesity is a leading risk factor for post-menopausal breast cancer, and this is concerning as 40% of cancer diagnoses in 2014 were associated with overweight/obesity. Despite this epidemiological link, the underlying mechanism responsible is unknown. We recently published that visceral adipose tissue (VAT) releases FGF2 and stimulates the transformation of skin epithelial cells.

A BET Bromodomain Inhibitor Suppresses Adiposity-Associated Malignant Transformation.

Almost half a million of all new cancers have been attributed to obesity and epidemiologic evidence implicates visceral adipose tissue (VAT) and high-fat diets (HFD) in increasing cancer risk. We demonstrated that VAT-derived fibroblast growth factor 2 (FGF2) from mice fed an HFD or obese individuals stimulates the malignant transformation of epithelial cells. Mechanism-based strategies to prevent this VAT-enhanced tumorigenesis have not been explored.

Elucidating the role of adipose tissue secreted factors in malignant transformation.

Although there is a growing number of incidences of obesity and obesity-linked cancers, how excess adiposity actually causes cancer has not been fully explained. Our previous study showed that removal of visceral adipose tissue significantly reduced the number of ultraviolet radiation (UVR)-initiated, high-fat diet-promoted skin cancers. This commentary focuses on our recently published study (Chakraborty, et al.

Deciphering metabolic rewiring in breast cancer subtypes.

Metabolic reprogramming, an emerging hallmark of cancer, is observed in breast cancer. Breast cancer cells rewire their cellular metabolism to meet the demands of survival, proliferation, and invasion. However, breast cancer is a heterogeneous disease, and metabolic rewiring is not uniform.

Parametrial fat tissue from high fat diet-treated SKH-1 mice stimulates transformation of mouse epidermal JB6 cells.

Unlabelled: Our previous studies indicated that decreasing visceral adipose tissue by surgical removal of the parametrial fat pads inhibited UVB-induced carcinogenesis in SKH-1 mice fed a high fat diet (HFD), but not a low fat diet (LFD) indicating that the parametrial fat tissue from mice fed a HFD played a role in skin carcinogenesis.

Objective: In the present study, we sought to investigate how a HFD may influence the intrinsic properties of the parametrial fat tissue to influence UVB-induced skin tumor formation.

Methods And Results: Immunohistochemical staining, adipokine array, and flow cytometry showed that parametrial fat tissue from mice fed a HFD had a higher density of macrophage-fused dead adipocytes (crown-like structures), more adipokines, and stimulated the production of more reactive oxygen species compared with parametrial fat tissue from mice fed a LFD.

PDE2 is a novel target for attenuating tumor formation in a mouse model of UVB-induced skin carcinogenesis.

Our previous studies demonstrated that the topical application of caffeine is a potent inhibitor of UVB-induced carcinogenesis and selectively increases apoptosis in tumors but not in non-tumor areas of the epidermis in mice that are at a high risk for developing skin cancer. While this effect is mainly through a p53 independent pathway, the mechanism by which caffeine inhibits skin tumor formation has not been fully elucidated. Since caffeine is a non-specific phosphodiesterase inhibitor, we investigated the effects of several PDE inhibitors on the formation of sunburn cells in mouse skin after an acute exposure to ultraviolet light B (UVB).

Toll-like receptor 3 activation is required for normal skin barrier repair following UV damage.

UV damage to the skin leads to the release of noncoding RNA (ncRNA) from necrotic keratinocytes that activates Toll-like receptor 3 (TLR3). This release of ncRNA triggers inflammation in the skin following UV damage. Recently, TLR3 activation was also shown to aid wound repair and increase the expression of genes associated with permeability barrier repair.

Innate immune sensors stimulate inflammatory and immunosuppressive responses to UVB radiation.

Almost 40 years from when it was first reported that UVB radiation exposure would modulate immune signaling, the photoimmunology field is still trying to understand the mechanisms by which UVB initiates inflammatory responses and modulates immune recognition. This commentary focuses on the ability of Toll-like receptors (TLRs), specifically TLR4 (Ahmad et al., 2014) and ligands such as damage-associated molecular patterns (DAMPs) released from injured cells to stimulate innate immune signaling and inflammatory cytokine production following UVB irradiation.

Inverse relationship between p53 and phospho-Chk1 (Ser317) protein expression in UVB-induced skin tumors in SKH-1 mice.

Immunohistochemical evaluation of serial stored paraffin sections from 42 keratoacanthomas and 11 squamous cell carcinomas demonstrated that skin tumors from UVB-exposed mice showed an inverse relationship (>95%) between p53 protein expression and phospho-Chk1 (Ser317), but not phospho-Chk1 (Ser345) protein expression. Tumors expressing high levels and large areas of p53 protein had no detectable phospho-Chk1 (Ser317), whereas tumors expressing high levels and large areas of phospho-Chk1 (Ser317) protein had no detectable p53. Squamous cell carcinomas that demonstrated heterogeneous p53 and phospho-Chk1 (Ser317) protein expression within the same tumor showed that areas expressing p53 were negative for phospho-Chk1 (Ser317) immunostaining while areas expressing phospho-Chk1 (Ser317) were negative for p53.