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Abstract: In a recent study, we found that male rats that minimally explored a novel environment as infants died significantly faster than their more exploratory brothers. At death, these males had various complex pathologies, precluding identification of specific hormonal mechanisms underlying adult disease progression and mortality. To minimize the variance of disease processes at the end of life, we conducted a longitudinal study with female Sprague–Dawley rats prone to high rates of spontaneous mammary and pituitary tumors. For females that developed either mammary or pituitary tumors, those that had been neophobic (least exploratory) as infants died approximately 6 months earlier than their neophilic (most exploratory) sisters. In the case of mammary tumors, both benign and malignant, neophobic females developed palpable tumors earlier than neophilic females, whereas the interval between first palpation and death was the same for all females, indicating psychosocial regulation of early rather than later stages of the disease. Neophobic females'' ovarian function aged more rapidly than their neophilic sisters. Concomitantly, they had lower corticosterone responses to restraint in late adulthood, ruling out high estrogen or corticosterone levels during senescence as causal factors in their accelerated mortality. During puberty, when mammary tissue is proliferating and differentiating, neophobic females experienced more irregular cycles with prolonged “luteal” phases, suggesting a role for prolactin, prolonged progesterone and fewer estrogen surges during this sensitive period for mammary tumor risk. Thus, we identified prolactin, estrogen, progesterone and possibly corticosterone dynamics as candidates for neuroendocrine mechanisms linking infant temperament with onset of adult neoplastic disease. [Copyright &y& Elsevier]

Emerging data suggest that p21-activated kinase 1 (Pak1), a downstream signaling molecule of the small GTPases, growth factors, and lipid signaling, is upregulated or hyperactivated in human breast cancer. Until now, however, no direct causative role had been found for Pak1 in mammary tumor formation. We therefore sought to identify the role that Pak1 plays in mammary gland tumorigenesis. Our results showed that in a transgenic mouse model, overexpression of catalytically active Pak1 leads to the development of malignant mammary tumors and to a variety of other breast lesions, including focal solid nodules, ductal hyperplasia, and mini-intraductal neoplasm and adenoma. We also found that Pak1 hyperactivation increases the stimulation of downstream proliferative signaling effectors MEK1/2 and p38-MAPK in mammary tumor epithelial cells. Moreover, in our study, we detected expression of estrogen receptor-alpha expression and progesterone receptor expression during early stages of the lesions, but their expression was lost during the cells' transition to malignant invasive tumors. Finally, we found that consistent with a role in breast tumor progression, Pak1 expression and its nuclear accumulation was increased progressively during the transition from ductal hyperplasia to ductal carcinoma in situ to adenocarcinoma in widely used multistep polyoma-middle T-antigen transgenic mice. Together, these findings provide the first direct evidence that Pak1 deregulation may be sufficient for the formation of mammary gland tumors.Oncogene (2006) 25, 2931–2936. doi:10.1038/sj.onc.1209309; published online 12 December 2005 [ABSTRACT FROM AUTHOR]

Hexachlorobenzene (HCB) is a widespread environmental pollutant. Controversy still exists about the breast carcinogenic properties of organochlorines in humans. The ligands, receptors, and related signaling proteins of the insulin growth factor family are involved in the regulation of breast-cancer cell growth. The aims of this study were to determine: (1) whether HCB is co-carcinogenic in a medium term assay of N-nitroso N-methylurea (NMU)-induced mammary tumors in rats; (2) the effect of HCB on insulin receptor (IR), insulin-like growth factor-I receptor (IGF-IR) and insulin receptor substrate-1 (IRS-1) levels and on IRS-1 phosphorylation; (3) microsomal and cytosolic Protein Tyrosine Kinase (PTK) activities in mammary glands and NMU-induced tumors. Sprague Dawley rats were injected with 50 mg/kg body weight of NMU at 50, 80, and 110 days old. HCB (100 mg/kg body weight) was administered three times a week from 65 to 110 days of age. Rats were separated in four groups: control, NMU, HCB, and NMU-HCB. HCB alone did not induce tumor development. Parameters of tumor development were increased in NMU-HCB compared to NMU rats. A higher cellular undifferentiation was observed in NMU-HCB tumors. IR, IGF-IR, and IRS-1 levels were higher in HCB than in controls. Conversely IGF-IR levels decreased in NMU-HCB vs. NMU group. The IRS-1 phosphorylation increased in HCB rats; however, it decreased in NMU-HCB vs. NMU. HCB decreased microsomal PTK activity in tumors. This study showed for the first time that HCB is a co-carcinogenic agent in NMU-induced mammary tumors in rats. Our results suggest that the IR and/or IGF-IR signaling pathway may be involved in the mechanism of action of HCB. [ABSTRACT FROM AUTHOR]

Abstract: Acrylamide is carcinogenic to experimental mice and rats, causing tumors at multiple organ sites in both species when given in drinking water or by other means. In mice, acrylamide increases the incidence of alveologenic lung tumors and initiates skin tumors after dermal exposures. In two bioassays in rats, acrylamide administered in drinking water consistently induced peritesticular mesotheliomas, thyroid follicular cell tumors, and mammary gland tumors, as well as primary brain tumors when all such tumors were included in data analysis. In one of the rat bioassays, increased numbers of adrenal pheochromocytomas, adenomas of pituitary and clitoral glands, papillomas of the oral cavity, and adenocarcinomas of the uterus also occurred. In both humans and experimental animals, a significant fraction of ingested acrylamide is converted metabolically to the chemically reactive and genotoxic epoxide, glycidamide, which is likely to play an important role in the carcinogenicity of acrylamide. No studies on the carcinogenicity of glycidamide have been published, but bioassays of this compound are in progress. Epidemiologic studies of possible health effects from exposures to acrylamide have not produced consistent evidence of increased cancer risk, in either occupationally exposed workers or the general populations of several countries in which acrylamide is present in certain foods and beverages. A doubling of risk for pancreatic cancer was observed in the most highly exposed workers within the largest industrial cohort, but no consistent exposure–response relationships were identified. Retrospective re-analyses of previously conducted case-control studies of cancer incidence in several European populations have identified no causal relationship between consumption of foods or beverages that contain acrylamide and the incidence of cancers at various sites including kidney, large bowel, urinary bladder, oral cavity, pharynx, larynx, esophagus, breast, and ovary. These retrospective studies of cancer incidence in relation to acrylamide in food have limited power to detect increased cancer risks, and have been criticized on various grounds, but they do indicate that no major cancer risks are attributable to intake of acrylamide in Western diets. [Copyright &y& Elsevier]

Canine mammary tumors (CMT) represent nearly half of bitch's neoplasias. The etiopathogeny of CMT is multifactorial. Both the protective effect of early ovarioectomy and steroid hormone receptors present in the tumor tissues show that the hormonal factor is involved in the development of mammary tumors. Clinical presentation of CMT may be unique or multiple, being the latter of the same or different histological type. The histopathological classification of tumors together with a brief description of their particular features is presented in this review. Although surgery is the best treatment for CMT, there are different adyuvant therapies that could improve the prognosis of the disease. The goal of the present work was to make an updated review of CMT, with special emphasis on its etiopathogy, treatment and new options resulting from the advances in molecular oncology. [ABSTRACT FROM AUTHOR]

Background and purpose: The primary objectives of this study were to address two major questions. (1) Does VEGF receptor-2 antibody (DC101) produce detrimental effects on tumor vascular function and oxygenation that could compromise adjuvant therapies? (2) Is pathophysiological response to such antiangiogenic strategies different in transplanted versus primary spontaneous tumors?Materials and methods: The effects of early and late initiation DC101 treatment were evaluated using spontaneous murine mammary carcinomas and two markedly different transplanted mammary tumors, MCa-35 and MCa-4. Mice were administered DC101 or saline, tumors were frozen, and immunohistochemical staining was quantified using image analysis of multiply-stained frozen sections. Total blood vessels were identified using antibodies to CD31 or panendothelial antigen, perfused vessels via i.v. injection of fluorescent DiOC7, and tumor hypoxia by hypoxia marker (EF5) uptake.Results: Tumor growth was significantly inhibited following DC101 administration in all tumor models. In general, early initiation DC101 treatment reduced perfused vessel counts and increased tumor hypoxia, while late initiation treatment had no significant impact on either. Results indicate that DC101 slows tumor growth through a decrease in vascular function, leading to increased tumor cell apoptosis and necrosis at sites distant from perfused blood vessels, and suggest that DC101 accelerates the rate at which tumor cells outgrow their functional vascular supply.Conclusions: Although highly variable among individual spontaneous tumors, the overall effects of DC101 on tumor hypoxia were quite similar between spontaneous and transplanted tumors. Since reductions in tumor oxygenation due to antiangiogenic treatment were transient, initial pathophysiological deficiencies that could compromise conventional therapies over the short-term may be of less relevance when administered over more extended treatment schedules. [Copyright &y& Elsevier]

OBJECTIVE:: The role of high fat diets in breast cancer/mammary tumor (MT) development is controversial. This may be partially attributable to variable effects of high fat diets on body weight. Here, we used a moderately high fat diet (32.5% fat calories) expected to cause obesity in most mice, but predicted to result in some mice remaining in the weight range of mice fed the low fat diet (11% fat calories). This provided the opportunity to compare mice fed the high fat diet exhibiting different body weights and mice of similar weight consuming high vs low fat diets. EXPERIMENTAL METHODS:: Transgenic MMTV-TGF-a mice, a model of postmenopausal breast cancer, consumed a low fat diet, that is, chow-fed (n=25) or a moderately high fat diet from 10 weeks of age (n=51). Body weight at 34 weeks of age was used to assign high fat diet mice to obesity-prone>overweight>obesity-resistant groups (n=17) (P<0.0001). Mice were euthanized when MTs developed or at 85 weeks of age. RESULTS:: Final body weights were highest in obesity-prone>overweight >obesity-resistant=chow-fed mice. Fat pads and fat pad:carcass were heaviest in obesity-prone followed by overweight mice. However, obesity-resistant mice had fat pad weights and fat pad:carcass three-fold greater than chow-fed mice. All groups had MT incidences between 72 and 82%. Obesity-prone mice exhibited the shortest MT latency (P<0.0001), but obesity-resistant mice had significantly shorter latency than chow-fed mice. CONCLUSIONS:: Consumption of a high fat diet increased adiposity and shortened MT latency in relation to its effect on body weight. These results indicate a complex role of dietary fat level on mammary tumorigenesis.International Journal of Obesity (2004) 28, 956-962. doi:10.1038/sj.ijo.0802664 [ABSTRACT FROM AUTHOR]

Conjugated linoleic acid (CLA) and the long-chain polyunsaturated n-3 fatty acids have been shown in vivo and in vitro to reduce tumor growth. Tumor growth could occur by slowing or stopping cell replication (by interfering with transition through the cell cycle), increasing cell death (via necrosis and/or apoptosis), or both. The anticancer effects of fatty acids, shown in vivo, could also be mediated by effects on the host's immune system. Although it is widely recognized that n-3 fatty acids can alter immune and inflammatory responses, considerably less is known about CLA. For n-3 fatty acids, several candidate mechanisms have been proposed for their immune effects, including changes in 1) membrane structure and composition, 2) membrane-mediated functions and signals (eg, proteins, eicosanoids), 3) gene expression, and 4) immune development. Considerable work has been done that shows the potential importance of CLA as an anticancer treatment; however, many questions remain as to how this effect occurs. This review summarizes the CLA and cancer literature and then uses the evidence for the anticancer immune and tumor properties of the long-chain n-3 fatty acids docosahexaenoic and eicosapentaenoic acids to suggest future research directions for mechanistic studies on CLA and cancer. [ABSTRACT FROM AUTHOR]

BRCA2 is a breast cancer susceptibility gene. Germline mutations of BRCA2 account for about 10-30% of familial breast cancer cases. Consistent with its tumor-suppressor activity, BRCA2 plays an important role in DNA repair. To assess the susceptibility of carriers of mutant BRCA2 to tumorigenesis induced by DNA-damaging carcinogens, we generated a Brca2 knockout mouse strain and studied its susceptibility to chemically induced tumorigenesis. Similar to previously reported Brca2 knockout mice, our Brca2-/- embryos die at E8.5-9.5, while the Brca2+/- mice are tumor-free and fertile. Unexpectedly, Brca2+/- mice developed tumors slower than did their wild-type littermates when treated with a potent carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). In vitro experiments showed that Brca2+/- mouse cells and Capan-1 cells, a human pancreatic cancer cell line deficient of BRCA2, were more sensitive to DMBA-induced apoptosis, than were Brca2+/+ mouse cells and a derivative of Capan-1 cells that expressed exogenous wild-type BRCA2, respectively. Our results suggest that enhanced sensitivity of Brca2 mutant cells to DMBA-induced apoptosis at the dose of DMBA we used contributes to the delayed tumorigenesis of Brca2+/- animals. This suggestion may also provide a rational explanation for a previous unexpected finding that cigarette smoking appears to reduce the breast cancer risk of BRCA2 mutation carriers.Oncogene (2004) 23, 1896-1901. doi:10.1038/sj.onc.1207314 Published online 23 February 2004 [ABSTRACT FROM AUTHOR]

Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor γ (PPARγ) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPARγ ligands. To evaluate the therapeutic potential of increased PPARγ signaling in vivo, we generated transgenic mice that express a constitutively active form of PPARγ in mammary gland. These mice are indistinguishable from their wild-type littermates. However, when bred to a transgenic strain prone to mammary gland cancer, bigenic animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite of their more malignant nature, bigenic tumors are more secretory and differentiated. The molecular basis of this tumor-promoting effect may be an increase in Wnt signaling, as ligand activation of PPARγ potentiates Wnt function in an in vivo model of this pathway. These results suggest that once an initiating event has taken place, increased PPARγ signaling serves as a tumor promoter in the mammary gland. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare mammary gland tumorigenesis in diabetic and non-diabetic rats. Streptozotocin and N-nitroso-N-methylurea were used to induce diabetes and mammary tumors, respectively. A suppression of mammary carcinogenesis in diabetic rats was shown by a longer latency period, a lower number of tumors per animal and a smaller final tumor volume. An 84% of the lesions developed in diabetic animals were benign tumors. Eighty day-old diabetic rats had significantly lower plasma levels of total-IGF-I and insulin versus non-diabetic rats. We postulate that the decrease in the total IGF-I and insulin levels during the promotion phase of carcinogenesis in this model plays an important role in retarding the tumor development in diabetic animals and in favoring the development of benign mammary lesions. [Copyright &y& Elsevier]

Terminal replicative senescence (TRS) is a physiological process associated with terminal differentiation, shortening of the telomere, and lack of proliferative activity. Immortalised and tumour cells have lost their differentiation potential and the ability to develop a senescence phenotype. Recently, others and we [11] have observed that some antitumour agents and radiation induce a senescence-like phenotype (SLP) in human immortalized and tumour cell lines. The main purpose of this study was to identify senescence-like cells (SLC) in mammary tumours of rats and assess whether chemopreventive agents that have been used for the prevention and/or treatment of breast cancer can induce a SLP in tumour cells. Sprague–Dawley rats with N-methyl-N-nitrosourea (MNU)-induced mammary tumours were randomised and treated with tamoxifen, vorozole, 4-(hydroxyphenyl)retinamide (4-HPR), or 9-cis-retinoic acid (9cRA). The SLC in mammary tumours were identified and characterised by: (a) SA-β-Gal staining method, which has been considered specific for human cells in TRS (b) staining for lipofuscin, which, although not specific, accumulates in the cytoplasm of cells in senescence; (c) lack of 5-Bromodeoxyuridine (BrdU) labelling after continuous (7 days) infusion of BrdU via osmotic pumps; (d) 90° side light scatter (9OLS) as evaluated by flow cytometry; and (e) decreased telomerase activity. We found that in control tumours, SA-β-Gal-positive cells were rare (below 1.0%) among the tumour cells, stroma fibroblast, myoepithelial and endothelial cells. SA-β-Gal-positive cells increased significantly in the tumours treated with chemopreventive agents and this was associated with a lack of proliferative activity, increased cell granularity, lipofuscin accumulation, and decreased telomerase activity. Thus, in this study we provide for the first time evidence that cells in replicative senescence are present in mammary tumours of rats and that chemopreventive agents can suppress tumor growth by a novel cellular mechanism, inducing a SLP in the tumor cells. [Copyright &y& Elsevier]

Purpose: We evaluated the radioprotective action of curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] extracted from Curcuma longa LINN against the acute and chronic effects and the mortality induced by exposure to radiation using female rats.Methods and Materials: For the assay of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in urine, a marker for acute effects, Wistar-MS virgin rats were fed the basal diet with exposure at 0 or 3 Gy to γ-rays from a 60Co source as the control. Rats in the experimental groups received whole-body irradiation with 3 Gy and were fed a diet containing 1% (wt/wt) curcumin for 3 days before and/or 2 days after irradiation. The urine was collected for a 24-h period between 1 and 2 days after irradiation. Urine samples were used to determine the 8-OHdG level using an enzyme-linked immunosorbent assay and the creatinine level by a modified Jaffe´ reaction. For long-term effects, rats at Day 17 of pregnancy were fed a diet containing curcumin for 3 days before and/or 3 days after irradiation with 1.5 Gy, and received a pellet of diethylstilbestrol as the promoter. The rats were examined for mammary and pituitary tumors for 1 year. To determine survival, virgin rats received whole-body irradiation with 9.6 Gy and were fed a diet containing curcumin for 3 days before and/or 3 days after irradiation. After irradiation, all rats were assessed daily for survival for 30 days.Results: Acutely in virgin rats irradiated with 3 Gy, the creatinine-corrected concentration and total amount of 8-OHdG in the 24-h urine samples were higher (approximately 1.3-fold) than the corresponding values in the nonirradiated controls. Adding curcumin to the diet for 3 days before and/or 2 days after irradiation reduced the elevated 8-OHdG levels by 50–70%. The evaluation of the protective action of curcumin against the long-term effects revealed that curcumin significantly decreased the incidence of mammary and pituitary tumors. However, the experiments on survival revealed that curcumin was not effective when administered for 3 days before and/or 3 days after irradiation (9.6 Gy).Conclusion: These findings demonstrate that curcumin can be used as an effective radioprotective agent to inhibit acute and chronic effects, but not mortality, after irradiation. [Copyright &y& Elsevier]

A single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of these tumors is preceded by a series of neuroendocrine disturbances, including attenuation of the preovulatory luteinizing hormone (LH) surge and amplification of the preovulatory 17β-estradiol surge, and gonadotropin-releasing hormone (GnRH) released in vitro. In this study, we examined the hypothesis that DMBA administration decreases levels of GnRH mRNA in the preoptic area-anterior hypothalamus (POA-AH) and GnRH receptor (GnRH Rc) mRNA and protein in the anterior pituitary gland. Sprague-Dawley rats, 55–60 days of age with regular estrous cycles, received a single dose of 15 mg DMBA in 1 ml sesame oil delivered by intragastric intubation. A first series of experiments was performed for the measurement of hypothalamic GnRH mRNA and pituitary GnRH Rc mRNA levels. A second series of experiments was performed for the measurement of pituitary GnRH receptor. In both experiments, animals were sacrificed by decapitation at 11.00, 16.00, 18.00 and 20.00 h on each day of the 7th or 8th estrous cycle (28–32 days) after treatment. GnRH and GnRH receptor mRNAs were quantified using solution hybridization-RNase protection assay. The GnRH Rc was quantified using the 125I-D-Ala6-N-Met-Leu6-des-Gly10-ethylamide GnRH. DMBA-treatment produced no significant effect on the overall mean values of GnRH mRNA. GnRH mRNA levels in control rats rose significantly between 16.00 and 20.00 h on proestrus and between 18.00 and 20.00 h on diestrus I. DMBA-treated rats had a surge in GnRH mRNA levels at 18.00 h on proestrus, and showed additional surges at 18.00 h on diestrus II and estrus. GnRH receptor mRNA content in the anterior pituitary gland surged at 16.00 h on certain days of the cycle in both groups of rats. In control rats, only the surge on diestrus II proved significant, whereas DMBA-treated rats exhibited significant surges on diestrus I, diestrus II and proestrus. GnRH receptor mRNA values were significantly lower on both days of diestrus in DMBA-treated rats compared with controls. GnRH Rc peptide content, like GnRH receptor in RNA surged at 16.00 h in both groups with the exception of a marked fall on proestrus day for DMBA treated rats. A reduction in the amplitude of the surge was also seen on the day of estrous and to a lesser extend on the day of diestrus DII in DMBA treated animal. Overall, there was a disruption of the GnRH Rc pattern which culminate on the day of proestrus in DMBA-treated animals. Interestingly, the daily rise between 11.00 and 16.00 h which is the more pronounced on the day of proestrus in control animals, was completely blunted in DMBA-treated rats. Overall, the results are consistent with the hypothesis that the carcinogen attenuates, directly or indirectly, preovulatory biosynthesis of the GnRH receptor and LH release. [ABSTRACT FROM AUTHOR]

Chloro-S-triazine herbicides [cyanazine (CZ), atrazine (AZ), simazine (SZ)] increase mammary tumors in Crl:CD®BR rats but not in F-344 rats or in mice. A nongenotoxic mechanism was investigated since the chloro-S-triazines are negative in short-term tests for genotoxicity. An in vivo battery was used to assess the chloro-S-triazines for estrogenic activity or for their ability to increase prolactin (PRL) levels, both of which play important roles in enhancing mammary gland tumorigenesis in rodents. Ovariectomized (OVX) female rats were treated with AZ, CZ, SZ, or three CZ metabolites for 4 days via intraperitoneal injection. The pattern of responses between the chloro-S-triazines and four controls (estradiol, estriol, haloperidol, reserpine) was compared. For the 6 endpoints examined, the responses from rats treated with AZ, CZ, SZ, and the metabolites of CZ most closely matched the responses from the reserpine-treated rats (a PRL rather than estrogenic mechanism). In addition, AZ, CZ, and SZ were tested in several other in vitro models (estrogen/ biogenic amine receptor competition assays and a yeast-expressed human estrogen receptor transcription assay) as well as an in vivo 24h timecourse experiment to characterize the CZ-induced increases in PRL levels. AZ, CZ, and SZ are not estrogen receptor (ER) activating compounds based on yeast transactivation and receptor competition data. CZ and AZ demonstrated marginal competition (at mM levels) to the D and α[sub 2] adrenergic receptors. Ligands to the D[sub 2] receptor, but not the α[sub 2] adrenergic receptor, are known to induce mammary tumors. CZ was also found to produce elevated PRL levels in a time-course similar to that seen with reserpine and haloperidol. Overall, the pattern of responses obtained with the chloro-S-triazines most closely matched the responses observed for reserpine. Taken together, these data suggest chloro-S-triazine-induced mammary tumors in rats are mediated through a... [ABSTRACT FROM AUTHOR]

Vorozole (Vz) is a competitive non-steroidal inhibitor of aromatase, which has been used to treat breast cancer in postmenopausal women and in various chemoprevention pre-clinical studies. Recently, we assessed the inhibitory effect of Vz on Mnu-induced mammary carcinogenesis (Lubet et al., 1994), as well as on the progression of mammary tumors (Lubet et al., 1998). In this study we evaluated the effects of Vz on tumor growth, serum estradiol, cell proliferation, apoptotic and non-apoptotic cell death to determine whether any of these 'surrogate’ markers might reflect the efficacy of various doses of Vz. Vz at doses of 2.5 (Hi), 0.32 (Md), and 0.08 (Lo) mg/kg body weight induced complete (100%), 60%, and 20% regression of mammary tumors, respectively. Vz at Hi and Md doses caused a decrease in serum estradiol within the first two days of treatment, and the estradiol values remained low with additional treatment for 4 and 10 days. When Vz was administered to animals bearing palpable tumors a time and dose-dependent decrease in the proliferating cells (BrdU-LI) was observed. The percentage of apoptotic cells (Al) sharply increased 2 days after initiation of Vz treatment and then decreased followed by an increase in non-apoptotic dead cells. Interestingly even the Lo dose of Vz, which was only moderately effective in suppressing tumor growth, decreased cell proliferation and increased cell death in the peripheral tumor areas at 4 and 10 days after initiation of treatment. The time- and dose-dependent alterations in various cell parameters suggest two different phases of Vz-induced cellular responses: (1) an early phase (2–4 days of treatment) with a sharp increase in apoptotic cells and decrease in proliferating cells, and (2) a later phase (10 days) with disintegration of tumor parenchyma, increase in non-apoptotic dead cells, and decrease in apoptotic cells. The dose-dependent decrease in proliferating cells and increase in apoptotic and non-apoptotic cell death in Vz-treated animals suggest that these biomarkers might be used as potential surrogate endpoints for efficacy in breast cancer chemoprevention and therapy studies with aromatase inhibitors. [ABSTRACT FROM AUTHOR]

Elastography is a sonographic technique that provides a noninvasive evaluation of the stiffness of a lesion. The objective of this work was to evaluate the accuracy of strain elastography, the most accessible modality in clinical practice, to discriminate between different histological types of malignant mammary neoplasms in the canine species, which can provide complementary information in real time to the diagnosis and thus help in the choice of surgical technique. A total of 34 females with 56 mammary carcinomas were selected and classified into three histological groups according to their aggressiveness. The histological and elastographic characteristics of these malignant tumors were analyzed and compared to evaluate the diagnostic accuracy of strain elastography. Visual score presented a sensitivity of 88.0%, specificity of 58.1%, and accuracy of 71.43% in distinguishing the most aggressive group of carcinomas. The strain ratio had a sensitivity of 84.0%, specificity of 61.1%, and accuracy of 69.64%. On the other hand, intratumoral strain ratio obtained a sensitivity of 71.40% and specificity of 61.90% when intratumoral fibrosis was taken as reference, with an accuracy of 66.07%. Similarly, peritumoral strain ratio was also positively related to fibrosis in the periphery of lesions (p ≤ 0.001), with a sensitivity of 93.80%, specificity of 77.50% and an accuracy of 92.87%. In conclusion, accuracy of this elastographic modality can be a useful method to differentiate more aggressive histological types. Therefore, it represents an additional diagnostic technique useful in the daily clinic thanks to the short time required for the examination, which allows real-time visualization and immediate interpretation of the results. [ABSTRACT FROM AUTHOR]

Breast cancer is the most prevalent tumor type among women and female dogs. Tumor malignancy is characterized by the epithelial-to-mesenchymal transition (EMT) which leads to the metastasis formation. The inhibition of angiotensin II type I receptor (AGTR1) by an antagonist such as losartan can suppress angiogenesis, consequently contributing to the metastasis control. The aim of this study was to analyze the capacity of losartan and AGTR-1 gene edition to modulate the EMT process in triple negative/metastatic mammary tumor cells, compared to existing treatment protocols such as carboplatin. The cell lines CF41.Mg and MDA-MB-468, were cultured and treated with carboplatin, losartan, or submitted to AGTR-1 gene edition by CRISPR/Cas9. EMT markers and PARP-1 protein and gene expression were evaluated by immunofluorescence or immunocytochemistry and qRT-PCR, respectively. Cell migration capacity was also evaluated. For CF41.Mg and MDA-MB-468 cell lines, there was an increase in E-cadherin and a decrease in N-cadherin and PARP-1 protein and gene expression after treatment with carboplatin, losartan, both in combination and after AGTR-1 gene edition. There was a decrease in VEGF and PARP-1 protein and gene expression after AGTR-1 gene edition. Moreover, in both lines, reduction in invasion rate was observed after all treatments. Our data suggest that losartan and the gene edition of AGTR-1 by CRISPR/Cas9 were able to block the DNA repair and control the EMT process, such as carboplatin. The results in the canine species are unprecedented, as there are no data in the literature that demonstrate the action of losartan in this tumor type. [ABSTRACT FROM AUTHOR]

Simple Summary: Canine malignant mammary tumor (MMT) is a prevalent malignancy in intact female dogs. A current lack of easily accessible tumor biomarkers hinders a timely assessment of the disease outcome. This study reveals that anterior gradient protein 2 (AGR2) is overexpressed in canine MMT tissues, and elevated levels of extracellular AGR2 in sera of MMT dogs are significantly associated with progression and remote metastasis of MMT and an unfavorable overall survival of the patients. Hence, serum eAGR2 level is significantly associated with an adverse outcome of MMT dogs and holds a predictive potential in MMT prognosis. Canine malignant mammary tumors (MMTs) are prevalent malignancy in intact female dogs with a high incidence of metastasis and recurrence. A current lack of easily accessible tumor biomarkers hinders a timely assessment of the disease outcome. We previously identified anterior gradient protein 2 (AGR2) with higher protein abundance in canine MMT tissues compared with normal counterparts. AGR2 is an endoplasmic reticulum-resident protein disulfide isomerase involved in the regulation of protein processing and also exists extracellularly via secretion to exert pro-oncogenic functions. In the present study, we validated overexpression of AGR2 in canine MMT tissues from 45 dogs using immunohistochemistry and immunoblotting, and assessed serum AGR2 levels in 81 dogs with MMTs and 21 benign cases using a competitive enzyme-linked immunosorbent assay (ELISA). Our data revealed that serum eAGR2 levels are significantly correlated with MMT progression (p = 0.0007) and remote tumor metastasis (p = 0.002). Moreover, elevated levels of serum eAGR2 are associated with an unfavorable overall survival of MMT dogs in later stage (p = 0.0158). Area under the time-dependent ROC curve (AUC) of serum eAGR2 level as a prognostic indicator was 0.839. Collectively, this study uncovered that serum eAGR2 level is significantly associated with an adverse outcome of MMT dogs and holds a predictive potential in MMT prognosis. [ABSTRACT FROM AUTHOR]

Understanding diet and energy balance as risk factors for breast, colon, and other cancers requires information on the contribution of each factor and of interactions among factors to cancer risk. Rodent models for breast cancer provide extensive data on effects of dietary fat and calories, energy balance, body weight gain, and physical activity on tumor development. Analyses of the combined data from many studies have shown clearly that quality and quantity of dietary fat and energy balance contribute independently to increased mammary gland tumorigenesis. These findings were seen in female rats fed diets high in fat (35-40% of calories) compared to rats fed control diets, with approximately 10% of calories as fat (Fay and Freedman, 1997, Breast Cancer Res. Treat. 46, 215-223). The methods used permit comparison of experimental and epidemiological data, and they may be useful in extrapolating between species and developing public health recommendations. In addition to the contributions of lifetime-diet composition, intake, energy balance, and physical activity to cancer risk, there are questions about the timing and duration of alterations in these factors and about the 'dose-response' characteristics of cancer risk to the factors. Endocrine mechanisms may be significant in mammary gland tumor risk, but experimental and epidemiological data indicate that cancers at other sites, such as colon and liver, also are influenced by the factors listed. Other diet and lifestyle factors that influence energy, or specifically fat, metabolism may also affect risk for cancers that are promoted by increased intake of fat and calories. Studies of separate and interactive effects of dietary fat, black tea, weight gain, and mammary gland tumorigenesis (Rogers, et al, 1998, Carcinogenesis 19, 1269-1273) have been analyzed. Using adjustment of carcinogenesis endpoints for body weight, tumor burden, and latency, they were found to be related to weight gain within treatment groups in 2 or 3 experiments. [ABSTRACT FROM PUBLISHER]

Previous studies on human breast cancer patients showed a decline in circulating melatonin levels corresponding to primary tumor growth and an increase when relapse occurred. The aim of the current investigation was to study in an experimental model possible mechanisms involved. Inbred female F344 Fischer rats were used for serial passages derived from a chemically induced mammary adenocarcinoma. Animals with slow-growing carcinosarcomas at passage 2 showed a significant elevation of nocturnal urinary melatonin (23.00–07.00 h; +50%, p < 0.05) and a nominal increase in plasma melatonin (+41%; 02.00–03.00 h). By contrast, these parameters were significantly depressed in animals with fast-growing sarcomas (urinary melatonin: –22%, p < 0.025; plasma melatonin: –56%, p < 0.01). At passage 2 nocturnal pineal N-acetylserotonin (02.00–03.00 h) was significantly enhanced (+62%, p < 0.05) probably due to an increased activity of serotonin-N-acetyltransferase (SNAT, +45%), the rate-limiting step of pineal melatonin biosynthesis converting serotonin to N-acetylserotonin. The activation of SNAT may be due to a stimulation of the sympathetic nervous system (urinary noradrenaline; NA: +243%, p < 0.005) when the cellular immune system responded towards tumor growth (urinary biopterin, +214%, p < 0.005). At passage 12 SNAT and N-acetylserotonin were unaffected but a depletion of plasma tryptophan (–34%, p < 0.0001), the precursor amino acid of melatonin, was found. The marginal decline in pineal serotonin (–18%, p < 0.05) disputes that the drastic depletion in circulating melatonin (–56%, p < 0.01) can be exclusively explained by a reduced availability of tryptophan. Therefore, the involvement of an additional mechanism has to be postulated, such as a degradation of melatonin via indoleamine 2,3-dioxygenase, an extrahepatic enzyme which has been detected in tumor tissue and is related to tryptophan 2,3-dioxygenase (TDO). TDO occurs only in the liver, is highly specific for L-tryptophan and is induced by glucocorticoids which would account for the observed depletion of plasma tryptophan resulting from a tumor-associated activation of the hypothalamo-pituitary-adrenal axis (urinary corticosterone +208%, p < 0.01). These findings present first explanations for the previously observed modulation of melatonin levels in cancer patients but also illustrate the high degree of complexity of mechanisms involved in the interactions between tumor growth and the immunoneuroendocrine system. [ABSTRACT FROM AUTHOR]

Five spontaneous canine mammary tumors were cultured in vitro and cell lines were established. The tumors included three frozen carcinomas, fine-needle aspirate from one fresh carcinoma, and one fresh atypical benign mixed tumor. The cell lines have so far been cultured for about 2 yr and passaged between 45 and 200 times. The cell lines expressed different types of intermediate filaments, including a heterogenous pattern. In some cases no intermediate filaments were expressed. Ultrastructure studies showed epithelial cells and cells intermediate between epithelial and myoepithelial types. Retrovirus associated A-particles were found in two carcinomas. The mixed mammary tumor cell line formed ductlike structures in collagen substrate. The cell lines grew when inoculated s.c. into male nude mice. Two carcinomas caused lymph node metastases in two mice and another carcinoma single lung metastases in one tested mouse. DNA hypodiploidy, studied by flow cytometry, in one of the primary carcinoma was retained in vitro, and this cell line showed polyploidy during later passages. The other cell lines had a more unstable DNA profile, although a tendency for polyploidy was found. These findings were also illustrated in chromosome studies. [ABSTRACT FROM AUTHOR]

A 1,1,2-triphenylbut-1-ene with a 4-OH group at one C-1 phenyl ring and a chlorocarbamate mustard moiety at the second C-1 ring (compound 3) was synthesized in order to obtain a 'cytotoxic estrogen' with a specific antitumor effect on estrogen-receptor-containing tumors. This compound was tested in comparison to the carrier (compound 1) and a compound (2) having a carbamate mustard group on both C-1 phenyl rings. The estrogen receptor affinity of compound 3 was only about one-quarter lower than that of compound 1, but much higher than that of compound 2. Compounds 2 and 3 showed only partially irreversible binding to the receptor owing to their relatively low alkylating properties. The growth inhibition of the receptor-positive MCF-7 breast cancer cell line by compound 3, but not by compound 1 or 2, was more pronounced than the inhibition of the receptor-negative line MDA. In vivo the hormone-dependent, transplantable mammary tumor MXT M3.2 of the mouse was much better inhibited by compound 3 than its hormone-resistent line MXT OVEX. Compounds 1-3 had no antiestrogenic properties in the mouse, but estrogenic activity was in the order 1>3>2. From these results and because the antitumor activity of compound 3 was superior to that of compounds 1 and 2 in the hormone-dependent tumor models, a selective, receptor-mediated cytotoxic effect of compound 3 on estrogen-receptor-positive tumors in obvious. [ABSTRACT FROM AUTHOR]

ErbB-3 and ErbB-4 are the most recently discovered and least characterized of the class I tyrosine kinase receptors. ErbB-3 is noteworthy for its low tyrosine kinase activity, suggesting that it may function more as an adaptor in signaling than as a kinase. Heregulin serves as a ligand for both receptors. A primary mechanism of heregulin action involves heterodimerization of its targeted receptors with other members of the class I family to promote cross-phosphorylation and cellular responses. Betacellulin also acts as a ligand for ErbB-4 to stimulate its kinase activity in both homo- and hetero-dimers. A new ligand (ASGP-2) for ErbB-2 has been discovered which operates by an intramembrane mechanism and may be able to modulate external ligand-dependent ErbB-3 or ErbB-4 heterodimeric interactions with ErbB-2. Heterodimerization stimulated by the ligands is a key feature of mitogenic signaling in mammary epithelial cells and tumors. Characterization of the signaling pathways for these receptors is still incomplete, but phosphatidylinositol 3-kinase and SHC have been implicated. Heregulin synthesized by the mesenchyme has been implicated in mammary development, modulated by systemic hormones. Observations on cultured mammary cells and mammary tumors have suggested linkages of ErbB-3 and ErbB-4 to proliferation and differentiation, respectively, but further work is needed to establish their definitive roles. [ABSTRACT FROM AUTHOR]

To tattoo human breast cancer prior to chemotherapy, radiotherapy, or surgery, thus allowing a better localization of the remaining tumor by the surgeon, we developed a formulation containing 10% charcoal suspended in water for parenteral preparations. The present study concerns a new step in the development of the charcoal suspension. We sought to determine whether the addition of various excipients could improve the formulation properties and affect the labeling of tumor by the suspension. We have tested surfactants (egg lecithin, polysorbate 80, Cremophor EL, and Pluronic F68), isotonisants (sugars such as glucose and mannitol), polysaccharides (dextrans 20 and 40), and Cabosil, a pyrogenated silica. Except for glucose and mannitol, which were added at a 5% concentration, the other excipients were added at a 0.1% concentration. they were dissolved in water for parenteral injection and sterilized at 120°C for 20 min. We then measured diffusion in vivo in mammary tumor. In vivo, when injected intratumorally in mice, a greater diffusion of charcoal particles was noted within the tumor (in the case of egg lecithin, polysorbate 80, dextran 20 and 40, and glucose) and sometimes in some organs (e.g., Cremophor EL and mannitol). Pluronic F68 slightly improved the stability of the suspension and did not lead to marked diffusion at the injection site, but it showed slight toxicity and cannot be used in the formulation. We concluded that the best formulation was an aqueous 10% micronized peat charcoal suspension. [ABSTRACT FROM AUTHOR]

A comprehensive chronic toxicity and carcinogenicity study was conducted on a series of Aroclors (1016, 1242, 1254, and 1260). Each Aroclor was assessed at multiple dietary concentrations, ranging from 25 to 200 ppm, for 24 months in male and female Sprague-Dawley rats. Liver toxicity was indicated by elevated serum enzyme activity (AST, ALT, and GGT), elevated serum cholesterol concentration, decreases in hematologic parameters (RBC, Hb, and Hct), hepatocellular hypertrophy, an increased incidence of altered hepatocellular foci, and an increased incidence of hepatocellular neoplasms (primarily adenomas). Liver toxicity was distinctly more severe in females than in males. The incidence of hepatocellular neoplasms was highly sex-dependent (females > males), differed between Aroclor mixtures and, for females, increased with dose and followed the general incidence pattern of Aroclor 1254 > Aroclor 1260 ≈ Aroclor 1242 > Aroclor 1016. A significant response (p < 0.05) in males was seen only for the high dose of Aroclor 1260. A small increase in the incidence of thyroid gland follicular cell adenomas was noted in males for Aroclors 1242, 1254, and 1260, with the incidence being uniform across dose groups and Aroclor mixtures. For females, increased survival relative to controls was observed for all Aroclor treatment groups. A significantly decreased trend in the incidence of mammary gland neoplasms compared to control was also noted for females receiving Aroclors 1242, 1254, and 1260. [ABSTRACT FROM PUBLISHER]

Design of diets for the study of dietary influences in mammary gland carcinogenesis requires attention to several questions: (1) Do the diets satisfy the nutritional needs of the animal under the conditions of the experiment, and are they palatable? (2) Does the protocol include determination of feed intake (if indicated) and of achievement of the desired level of nutrient deficiency, adequacy, or excess? (3) Are there potentially confounding nutrient interactions or nutrient effects or physiological or pathological responses that must be considered? The particular sensitivity of mammary gland tumorigenesis to intake of fat and calories and to body weight gain must be considered and controlled for in all experiments. [ABSTRACT FROM AUTHOR]

An investigation of the specific localization of estrogen receptors in frozen sections of mammary tumors using an estrogen-BSA-FITC complex is presented. The results are discussed in relation to the existing literature. Although the fluorescence is certainly not due to interaction with type I receptors, the reaction is not as non-specific as is suggested sometimes in the literature. It is likely that type II receptors are involved, which are probably localized at the same site as type I receptors. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether or not endogenous mammary peroxidase can serve as a cytochemical marker to distinguish ovarian hormone-dependent from ovarian hormone independent mammary tumors. Spontaneous mammary tumors arising in virgin C3H and GR mice (hormone independent tumors) and hormone-dependent mammary tumors arising during pregnancy in GR mice were examined. None of these tumors contained mammary peroxidase. Mammary tumors induced in Sprague-Dawley rats with methylnitrousourea (MNU) and dimethylbenzanthracene (DMBA) were also examined. These tumors included hormone-dependent and hormone independent ones. Several of the DMBA-induced hormonedependent tumors contained a few peroxidase-positive cells, but the hormone independent tumors were negative. All of the MNU-induced tumors examined were negative for mammary peroxidase. Twenty human breast tumors (malignant and non-malignant) removed from women at surgery, were also negative for mammary peroxidase. Our results indicate that endogenous mammary peroxidase cannot be used to distinguish hormone-dependent from hormone independent mammary tumors. [ABSTRACT FROM AUTHOR]

Background: The most aggressive breast cancer is the triple negative histological type, and the gold standard for its treatment is platinum salts, such as carboplatin. Due to high recurrence, there is a need to test new drugs, such as PARP inhibitors (PARPi), that induce lethality in cells with DNA damage. Olaparib is a PARPi, already used in some tumors but not tested in canine species. Thus, the aim of this study was to demonstrate the efficacy of olaparib in inhibiting DNA repair and control disease progression by decreasing the migration capacity of mammary tumor cells., Methods: The cell lines CF41.Mg and MDA-MB-468 were cultured and MTT was performed to define the best dose of carboplatin. Next, the cells were treated with 10 μM carboplatin, olaparib, and with a combination of both for 24 hours. PARP-1 protein and gene expression were evaluated by immunofluorescence, western blotting, and qRT-PCR, respectively. The analysis of cell migration was performed in transwell chambers., Results: For CF41.Mg and MDA-MB-468 cell lines, there was a decrease in PARP-1 protein and gene expression after treatment with carboplatin, olaparib, and both in combination compared to the group without treatment (control) (p<0.05). Moreover, in both lines, a reduction in invasion rate was observed after treatment with carboplatin, olaparib and when combined, compared to the control group (p<0.05)., Conclusion: Our data suggest that carboplatin and olaparib were able to block DNA repair and control the cancer invasion, especially when used in combination. The results with olaparib in the canine line are unpublished. The olaparib should be a possible agent against human breast cancer and canine mammary tumors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Development and progression of breast cancer is an outcome of strong interplay between proto-oncogenes as well as environmental factors. Among proto-oncogenes, c-myc , a multifunctional transcription factor (TF), is one of the most highlighted one, whereas among environmental factors Mouse Mammary Tumor Virus (MMTV)-like virus is a widely discussed agent. Both, c-myc and MMTV-like virus, are known to individually correlate with the poor prognosis of breast cancer. However, no study has ever been reported to determine their mutual association in breast cancer patients. In this study, our aim was to quantify and compare c-myc mRNA in MMTV-like virus-positive and virus-negative-histopathological types of breast cancer. At first, biopsy samples of 105 breast cancer patients with known histopathological types were collected and screened for the presence of MMTV-like virus. To quantify mRNA level of c-myc , quantitative-Polymerase Chain Reaction (qPCR) was used. Next, c-myc expression was compared in MMTV-like virus-positive and virus-negative-histopathological types as of breast cancer. Statistical analysis was done using GraphPad Prism 7 Software. Molecular analysis revealed that 69 (65.72%) out of 105 samples were positive for MMTV-like virus. Moreover, invasive types of breast cancer exhibited increased (3–13 folds higher) expression of c-myc as compared to baseline representing normal control comprising of 15 tumor-free biopsy samples of breast cancer patients. Whereas, non-invasive types of breast cancer showed only 1–3 folds increase in the expression of c-myc as compared to normal control. Furthermore, virus-positive and virus-negative samples had different levels of c-myc mRNA. Positive status of MMTV-like virus was noticed to significantly associate with c-myc expression increasing it from 1.87-folds in virus-negative patient samples to 4.31-folds in virus-positive patient samples (p -value: <0.0001). Whereas, increase in the expression of c-myc was only 1.14-folds higher in 2 (13.33%) virus-positive-normal control samples as compared to 13 (86.67%) virus-negative-normal control samples (P -value: <0.01). In conclusion, it is suggested that presence of MMTV-like virus and over-expression of c-myc may be used as markers of invasion of breast cancer. • Development and progression of breast cancer is an outcome of strong interplay between proto-oncogenes as well as environmental factors. • Both, c-myc , a proto-oncogene and MMTV-like virus, are known to individually correlate with the invasiveness of breast cancer. • This study aimed to quantify and compare c-myc mRNA in MMTV-like virus positive and negative-histopathological types as of breast cancers. • Expression of c-myc was only 1.14-folds in 2 (13.33%) virus-positive-normal controls as compared to 13 (86.67%) virus-negative-normal controls. • The presence of MMTV-like virus and over-expression of c-myc may be used as markers of invasion of breast cancer [ABSTRACT FROM AUTHOR]

This retrospective study aimed to reveal the series of neoplasms in dogs treated at the Oncology Service of a university veterinary hospital, including 535 dogs. There was a higher prevalence of tumors in females (71%), perhaps due to high incidence of mammary tumors which accounted for 39% of the total. Among the therapeutic measures, surgical procedures (46%) were the most used compared with the others therapies. This study elucidates the high number of various types of tumors cases that affect dogs, with the need for early and accurate diagnosis, allowing better adaptation to the therapeutic, and draw the attention of veterinarians to the constant updating of knowledge on this topic. [ABSTRACT FROM AUTHOR]

Simple Summary: Shear wave elastography (SWE) is a new diagnostic method allowing for a non-invasive differential diagnosis between benign and malignant mammary tumors. Mammary tumors in dogs are often hormone-dependent, and a surgical approach is currently the most recommended method for the treatment of mammary neoplasia. However, preoperative, pharmacological therapy eliminating hormonal stimulation can sometimes be indicated to reduce the size of the tumor and facilitate subsequent surgery. The aim of this study was to evaluate the influence of the reduction in the benign tumor size observed after treatment with the use of aglepristone on the shear wave elastography results, obtained before and after therapy. We noticed that a fast and significant reduction in tumor size, as a consequence of preoperative pharmacological treatment, did not influence the diagnosis performed using the SWE technique. These results seem to indicate the accuracy and usefulness of this new diagnostic method, and confirm the hypothesis that tumor tissue density is a valuable parameter when determining the benignancy of mammary tumors in dogs. Shear wave elastography (SWE) can be useful to discriminate between malignant and benign mammary tumors. In dogs with elevated progesterone levels compared to the baseline and fast-growing tumors, treatment with the use of aglepristone allows for tumor size reduction, which facilitates surgery. This study aimed to evaluate the influence of the preoperative treatment of benign mammary tumors (BMTs), performed with the use of aglepristone, on the density of the tumor tissue measured by SWE. Twelve female dogs with diagnosed BMTs and increased levels of progesterone were treated with aglepristone (Alizine, Virbac, France) at 10 mg/kg s.c. (Subcutaneous injection). twice, with a 24 h interval. The density of the tumor was evaluated by SWE before and after the treatment. The type of tumor was evaluated by fine needle aspiration cytology before treatment, and a histopathological examination was made after surgical removal, performed after the aglepristone treatment. In all the cases, a significant reduction in the mammary tumor's size was observed following treatment, with no influence on the density of the tumor's tissue measured by SWE. Similar studies on malignant mammary tumors are warranted to verify if in these cases, density will also be a constant parameter that is not dependent on the tumor size. [ABSTRACT FROM AUTHOR]

Simple Summary: The PTEN/AKT pathway is involved in several human and animal tumors' pathogenesis. This study investigates the PTEN/AKT pathway's biological and prognostic values in canine and feline mammary tumors. PTEN, phospho-AKT (p-AKT) and Rictor expression was determined by immunohistochemistry in canine mammary adenomas and carcinomas and feline mammary carcinomas. In mammary tumors of both species p-Akt was inversely correlated with PTEN expression and positively with Rictor expression; p-Akt and Rictor expression correlated with poorer prognosis. This data could provide a rationale for further studies of this pathway in veterinary oncology due to prognostic and therapeutic implications. Phosphatase and tensin homolog deleted on chromosome10 (PTEN), phospho-v-Akt murine thymoma viral oncogene homolog (AKT), and the Rapamycin-Insensitive Companion of mTOR (Rictor) expression was investigated by immunohistochemistry in 10 canine mammary adenomas (CMAs), 40 canine mammary carcinomas (CMCs), and 30 feline mammary carcinomas (FMCs). All the CMAs, 25 of 40 CMCs (63%) and 7 of 30 FMCs (23%), were PTEN-positive. In dogs, no CMAs and 15 of 25 CMCs (37%) expressed phospho-AKT (p-AKT), while 24 of 30 FMCs (82%) were p-AKT-positive. One of 10 CMAs (10%), 24 of 40 CMCs (60%) and 20 of 30 FMCs (67%) were Rictor-positive. In the dog, PTEN expression correlated with less aggressive tumors, absence of lymphatic invasion, and longer survival. P-AKT expression correlated with more aggressive subtype, lymphatic invasion, and poorer survival and Rictor expression with lymphatic invasion. In cats, PTEN correlated with less aggressive carcinomas, absence of lymphatic invasion, and better survival. P-AKT and Rictor expression correlated with poorer survival. PTEN expression was inversely correlated with p-AKT and Rictor in both species, while p-AKT positively correlated with Rictor expression. A strong PTEN/AKT pathway involvement in behavior worsening of CMT and FMTs is demonstrated, providing a rationale for further studies of this pathway in veterinary oncology. [ABSTRACT FROM AUTHOR]

1,2-dichloroethane (DCE or EDC) is a chlorinated hydrocarbon used as a chemical intermediate, including in the synthesis of polyvinyl chloride. Although DCE has induced tumors in both rats and mice, the overall weight-of-evidence suggests a lack of in vivo mutagenicity. The present study was conducted to explore a potential mode of action further for tumor formation in rat mammary tissue. Fischer 344 rats were exposed to target concentrations of 0 or 200 ppm of DCE vapors (6 hours/day, 7 days/week) for at least 28 days; 200 ppm represents a concentration of ~20% higher than that reported to induce mammary tumors. Endpoints examined included DNA damage (via Comet assay), glutathione (reduced, oxidized and conjugated), tissue DNA adducts, cell proliferation and serum prolactin levels. Exposure to DCE did not alter serum prolactin levels with consistent estrous stage, did not cause cell proliferation in mammary epithelial cells, nor result in histopathological alterations in the mammary gland. DNA adducts were identified, including the N 7 -guanylethyl glutathione adduct, with higher adduct levels measured in liver (nontumorigenic target) compared with mammary tissue isolated from the same rats; no known mutagenic adducts were identified. DCE did not increase the Comet assay response in mammary epithelial cells, whereas DNA damage in the positive control (N-nitroso-N-methylurea) was significantly increased. Although the result of this study did not identify a specific mode of action for DCE-induced mammary tumors in rats, the lack of any exposure-related genotoxic responses further contributes to the weight-of-evidence suggesting that DCE is a nongenotoxic carcinogen., (© 2020 John Wiley & Sons, Ltd.)