BackgroundObesity is correlated with an increased risk for developing postmenopausal breast cancer. Since obesity rates continue to rise worldwide, it is important to understand how the obese microenvironment influences normal mammary tissue to increase breast cancer risk. We hypothesized that obesity increases the proportion of luminal progenitor cells, which are thought to be the cells of origin for the most common types of breast cancer, potentially leading to an increased risk for breast cancer.MethodsTo study the obese microenvironment within the mammary gland, we used a high-fat diet mouse model of obesity and human breast tissue from reduction mammoplasty surgery. We identified changes in breast epithelial cell populations using flow cytometry for cell surface markers, in vitro functional assays and expression of markers on breast tissue sections.ResultsIn both obese female mice and women, mammary epithelial cell populations demonstrated significant decreases in basal/myoepithelial cells, using either flow cytometry or cell-type-specific markers (SMA and p63). Estrogen receptor alpha (ERα) expression was significantly increased in luminal cells in obese mammary tissue, compared with control mice or breast tissue from lean women. Functional assays demonstrated significantly enhanced mammary epithelial progenitor activity in obese mammary epithelial cells and elevated numbers of ERα-positive epithelial cells that were co-labeled with markers of proliferation. Weight loss in a group of obese mice reversed increases in progenitor activity and ERα expression observed in obese mammary tissue.ConclusionsObesity enhances ERα-positive epithelial cells, reduces the number of basal/myoepithelial cells, and increases stem/progenitor activity within normal mammary tissue in both women and female mice. These changes in epithelial cell populations induced by obesity are reversible with weight loss. Our findings support further studies to examine how obesity-induced changes in stem/progenitor cells impact breast tumor incidence and histologic tumor types.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0921-7) contains supplementary material, which is available to authorized users.

Obese women diagnosed with breast cancer have an increased risk for metastasis, and the underlying mechanisms are not well established. Within the mammary gland, adipose-derived stromal cells (ASCs) are heterogeneous cells with the capacity to differentiate into multiple mesenchymal lineages. To study the effects of obesity on ASCs, mice were fed a control diet (CD) or high-fat diet (HFD) to induce obesity, and ASCs were isolated from the mammary glands of lean and obese mice. We observed that obesity increased ASCs proliferation, decreased differentiation potential, and upregulated expression of α-smooth muscle actin, a marker of activated fibroblasts, compared to ASCs from lean mice. To determine how ASCs from obese mice impacted tumor growth, we mixed ASCs isolated from CD- or HFD-fed mice with mammary tumor cells and injected them into the mammary glands of lean mice. Tumor cells mixed with ASCs from obese mice grew significantly larger tumors and had increased invasion into surrounding adipose tissue than tumor cells mixed with control ASCs. ASCs from obese mice demonstrated enhanced tumor cell invasion in culture, a phenotype associated with increased expression of insulin-like growth factor-1 (IGF-1) and abrogated by IGF-1 neutralizing antibodies. Weight loss induced in obese mice significantly decreased expression of IGF-1 from ASCs and reduced the ability of the ASCs to induce an invasive phenotype. Together, these results suggest that obesity enhances local invasion of breast cancer cells through increased expression of IGF-1 by mammary ASCs, and weight loss may reverse this tumor-promoting phenotype.

Spontaneous tumors in dogs share many of the same features of their human orthologues including clinical behavior, response to treatment, and molecular defects. It is therefore natural to consider the use of dogs and their spontaneous malignancies in the study of complex disease such as cancer. Scottish Deerhounds are a giant breed of dogs that exhibit a high incidence of bone cancer. Our previous work suggested that osteosarcoma within this breed could be explained by the presence of a major gene of dominant effect. Herein, we use a whole genome mapping approach to evaluate a four-generation pedigree of Scottish Deerhounds for linkage of their osteosarcoma phenotype. Using this approach we found evidence of linkage (Z(max)=5.766) between their phenotype and markers located on CFA34, in a region syntenic to human chromosome 3q26. The identification of this locus provides novel insight into the genetic basis of osteosarcoma in both canines and humans.

◥Obesity enhances breast cancer risk in postmenopausal women and premenopausal women with genetic or familial risk factors. We have shown previously that within breast tissue, obesity increases macrophage-driven inflammation and promotes expansion of luminal epithelial cell populations that are hypothesized to be the cells of origin for the most common subtypes of breast cancer. However, it is not clear how these changes within the microenvironment of the breast alter cancer risk and tumor growth. Using a high-fat diet to induce obesity, we examined preneoplastic changes associated with epithelial cell-specific loss of Trp53. Obesity significantly enhanced the incidence of tumors of diverse histotypes and increased stromal cells within the tumor microenvironment. Obesity also promoted the growth of preneoplastic lesions containing elevated numbers of luminal epithelial progenitor cells, which were surrounded by macrophages. To understand how macrophage-driven inflammation due to obesity enhances tumor formation, mice were treated with IgG or anti-F4/80 antibodies to deplete macrophages during preneoplastic growth. Unexpectedly, depletion of macrophages in obese mice enhanced mammary epithelial cell stem/progenitor activity, elevated expression of estrogen receptor alpha, and increased DNA damage in cells. Together, these results suggest that in obesity, macrophages reduce epithelial cells with DNA damage, which may limit the progression of preneoplastic breast lesions, and uncovers complex macrophage function within the evolving tumor microenvironment. Understanding how obesity alters the function of macrophages during tumor formation may lead to chemoprevention options for at-risk obese women.Significance: Understanding how obesity impacts early tumor growth and response to macrophage-targeted therapies may improve therapeutics for obese patients with breast cancer and identify patient populations that would benefit from macrophagetargeted therapies.

Obesity is a risk factor for breast cancer in postmenopausal and high‐risk premenopausal women. Changes within the obese breast microenvironment may increase breast cancer risk. Transforming growth factor beta‐1 (TGFβ1) is a major regulator of mammary epithelial stem/progenitor cells, and its activity is dysregulated under conditions of obesity. Using a high‐fat diet model of obesity in mice and breast tissue from women, we observed that TGFβ1 activity is reduced in breast epithelial cells in obesity. Breast ducts and lobules demonstrated increased decorin in the extracellular matrix (ECM) surrounding epithelial cells, and we observed that decorin and latent TGFβ1 complexed together. Under conditions of obesity, macrophages expressed higher levels of decorin and were significantly increased in number surrounding breast epithelial cells. To investigate the relationship between macrophages and decorin expression, we treated obese mice with either IgG control or anti‐F4/80 antibodies to deplete macrophages. Mice treated with anti‐F4/80 antibodies demonstrated reduced decorin surrounding mammary ducts and enhanced TGFβ1 activity within mammary epithelial cells. Given the role of TGFβ1 as a tumor suppressor, reduced epithelial TGFβ1 activity and enhanced TGFβ1 within the ECM of obese mammary tissue may enhance breast cancer risk.

A 20-year-old, female Catalina macaw (Ara ararauna × Ara macao ) was presented with bilateral uveitis and hyphema. The hyphema initially improved with 0.12% prednisolone acetate ophthalmic drops (1 drop OU q4h for 7 days), but the hyphema recurred after the drops were tapered. The bird subsequently developed inappetance, weight loss, regurgitation, and lethargy and was euthanatized 24 days after initial presentation. Necropsy revealed marked splenomegaly and hepatomegaly, with significant mucosal ulcerations of the proventriculus and petechiation associated with both kidneys. Histopathologic examination revealed multicentric lymphoma, with neoplastic cells observed in ocular, splenic, hepatic, renal, proventricular, intestinal, pancreatic, and choanal tissue. Neoplastic lymphocytes effaced the iris, ciliary body, and the choroid of the eyes, and neoplastic lymphocytes were attached to the corneal endothelium and infiltrated the sclera, episclera, and conjunctivae. Immunohistochemical results indicated that the neoplastic lymphocytes were CD3(+) and CD79a(-), which is consistent with T-cell lymphoma.

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Teratomas are germ cell neoplasms derived from 2 or more of the totipotential cell lines (ectoderm, mesoderm, endoderm). 5 The gonads are the most common location for development of teratomas in human beings and animals; however, these tumors can also develop at extragonadal locations, usually along the midline axis of the body. 5,13 Extragonadal teratomas have been infrequently reported in wild and domestic animals involving cutaneous structures, the alimentary tract, the kidneys, and retroperitoneal space, as well as other systems. 2,8,15,21 Descriptions of teratomas of the central nervous system are rare in both human beings and animals.17 Spinal teratomas in human beings are more common in pediatric patients, in whom they are typically observed in the sacrococcygeal region. 10,11,17 These tumors tend to be cystic, extradural structures localized proximal to the sacrum. In contrast, teratomas of the spinal cord in adults are usually found in the thoracolumbar spine. 17 Intraspinal teratomas account for 3%-9% of all intraspinal tumors in children, and although it is not possible to determine their incidence in domestic animals, reports of these conditions are exceedingly rare. 4 A recent report described a cervical spinal cord teratoma in a Giant Schnauzer and summarized the literature on canine intraspinal teratomas. 25In the ferret, teratomas have been described in the ovaries, uterus, and adrenal glands (Williams B: 1996, Bilateral adrenal teratomas in a domestic ferret (Mustela putorius furo). Vet Pathol 33:587. Abstract). 3,19,24 The current report describes the clinical, radiographic, and microscopic features of an intramedullary teratoma in a domestic ferret.An 18-month old, female, spayed domestic ferret (Mustela putorius furo) weighing 415 g presented to the University of Wisconsin, School of Veterinary Medicine (UWVMTH; Madison, Wisconsin) with a 2-week history of anorexia and lethargy. The ferret was fed a commercial ferret diet and lived in a large cage with 6 other ferrets. The owners reported that 1 week prior to presentation, the ferret seemed weak in the hind legs and could no longer climb. The ferret had been examined by the referring veterinarian (RDVM) 5 days prior to presentation for diarrhea, which coincided with the onset of hind limb paresis. The results of a plasma biochemistry panel determined by the RDVM were consistent with a mild hypoalbuminemia (2.6 g/dl, reference interval: 3.4-4.8 g/dl) and mild hyperglobulinemia (3.2 g/dl, reference interval: 0.2-2.4 g/dl). The results of a complete blood cell count (CBC) were unremarkable. The RDVM prescribed metronidazole (22 mg/kg orally every 12 hr) for the diarrhea. Despite medical therapy, there was no significant improvement in clinical signs, and the ataxia progressed.On presentation to the UWVMTH, the ferret was alert and mentally appropriate but small for its age and cachexic (body condition score of 1.5/9), with pronounced generalized muscle wasting. The perineal skin was hyperemic and wet from urine scalding, and the anus was swollen...