Mammary Neoplasia Research Articles

Targeting Aberrant p70S6K Activation for Estrogen Receptor-Negative Breast Cancer Prevention.

The prevention of estrogen receptor-negative (ER-) breast cancer remains a major challenge in the cancer prevention field, although antiestrogen and aromatase inhibitors have shown adequate efficacy in preventing estrogen receptor-positive (ER+) breast cancer. Lack of commonly expressed, druggable targets is a major obstacle for meeting this challenge. Previously, we detected the activation of Akt signaling pathway in atypical hyperplasic early-stage lesions of patients. In the current study, we found that Akt and the downstream 70 kDa ribosomal protein S6 kinase (p70S6K) signaling pathway was highly activated in ER- premalignant breast lesions and ER- breast cancer. In addition, p70S6K activation induced transformation of ER- human mammary epithelial cells (hMEC). Therefore, we explored the potential of targeting Akt/p70S6K in the p70S6K activated, ER- hMEC models and mouse mammary tumor models for the prevention of ER- breast cancer. We found that a clinically applicable Akt/p70S6K dual inhibitor, LY2780301, drastically decreased proliferation of hMECs with ErbB2-induced p70S6K activation via Cyclin B1 inhibition and cell-cycle blockade at G0-G1 phase, while it did not significantly reverse the abnormal acinar morphology of these hMECs. In addition, a brief treatment of LY2780301 in MMTV-neu mice that developed atypical hyperplasia (ADH) and mammary intraepithelial neoplasia (MIN) lesions with activated p70S6K was sufficient to suppress S6 phosphorylation and decrease cell proliferation in hyperplasic MECs. In summary, targeting the aberrant Akt/p70S6K activation in ER- hMEC models in vitro and in the MMTV-neu transgenic mouse model in vivo effectively inhibited Akt/S6K signaling and reduced proliferation of hMECs in vitro and ADH/MIN lesions in vivo, indicating its potential in prevention of p70S6K activated ER- breast cancer. Cancer Prev Res; 10(11); 641-50. ©2017 AACR.

MicroRNAs in the development and neoplasia of the mammary gland

Study on the role of microRNAs (miRs) as regulators of gene expression through posttranscriptional gene silencing is currently gaining much interest,due to their wide involvement in different physiological processes. Understanding mammary gland development, lactation, and neoplasia in relation to miRs is essential. miR expression profiling of the mammary gland from different species in various developmental stages shows their role as critical regulators of development. miRs such as miR-126, miR-150, and miR-145 have been shown to be involved in lipid metabolism during lactation. In addition, lactogenic hormones influence miR expression as evidenced by overexpression of miR-148a in cow mammary epithelial cells, leading to enhanced lactation. Similarly, the miR-29 family modulates lactation-related gene expression by regulating DNA methylation of their promoters. Besides their role in development, lactation and involution, miRs are responsible for breast cancer development. Perturbed estrogen (E2) signaling is one of the major causes of breast cancer. Increased E2 levels cause altered expression of ERα, and ERα-miR cross-talk promotes tumour progression. miRs, such as miR-206, miR-34a, miR-17-5p, and miR-125 a/b are found to be tumour suppressors; whereas miR-21, miR-10B, and miR-155 are oncogenes. Oncogenic miRs like miR-21, miR-221, and miR-210 are overexpressed in triple negative breast cancer cases which can be diagnostic biomarker for this subtype of cancer. This review focuses on the recent findings concerning the role of miRs in developmental stages of the mammary gland (mainly lactation and involution stages) and their involvement in breast cancer progression. Further studies in this area will help us to understand the molecular details of mammary gland biology, as well as miRs that could be therapeutic targets of breast cancer.

Pathobiology of the 129:Stat1\u2212/\u2212 mouse model of human age-related ER-positive breast cancer with an immune infiltrate-excluded phenotype

BackgroundStat1 gene-targeted knockout mice (129S6/SvEvTac-Stat1tm1Rds) develop estrogen receptor-positive (ER+), luminal-type mammary carcinomas at an advanced age. There is evidence for both host environment as well as tumor cell-intrinsic mechanisms to initiate tumorigenesis in this model. In this report, we summarize details of the systemic and mammary pathology at preneoplastic and tumor-bearing time points. In addition, we investigate tumor progression in the 129:Stat1−/− host compared with wild-type 129/SvEv, and we describe the immune cell reaction to the tumors.MethodsMice housed and treated according to National Institutes of Health guidelines and Institutional Animal Care and Use Committee-approved methods were evaluated by histopathology, and their tissues were subjected to immunohistochemistry with computer-assisted quantitative image analysis. Tumor cell culture and conditioned media from cell culture were used to perform macrophage (RAW264.7) cell migration assays, including the 129:Stat1−/−-derived SSM2 cells as well as control Met1 and NDL tumor cells and EpH4 normal cells.ResultsTumorigenesis in 129:Stat1−/− originates from a population of FoxA1+ large oval pale cells that initially appear and accumulate along the mammary ducts in segments or regions of the gland prior to giving rise to mammary intraepithelial neoplasias. Progression to invasive carcinoma is accompanied by a marked local stromal and immune cell response composed predominantly of T cells and macrophages. In conditioned media experiments, cells derived from 129:Stat1−/− tumors secrete both chemoattractant and chemoinhibitory factors, with greater attraction in the extracellular vesicular fraction and inhibition in the soluble fraction. The result appears to be recruitment of the immune reaction to the periphery of the tumor, with exclusion of immune cell infiltration into the tumor.Conclusions129:Stat1−/− is a unique model for studying the critical origins and risk reduction strategies in age-related ER+ breast cancer. In addition, it can be used in preclinical trials of hormonal and targeted therapies as well as immunotherapies.

Transcriptomic profile reveals molecular events associated to focal adhesion and invasion in canine mammary gland tumour cell lines.

The prevalence of cancer in animals has increased significantly over the years. Mammary tumours are the most common neoplasia in dogs, in which around 50% are presented in the malignant form. Hence, the development and characterization of in vitro models for the study of canine tumours are important for the improvement of cancer diagnosis and treatment. Thus, the aim of this study was to characterize cell lines derived from canine mammary gland neoplasias which could be further used for basic and applied oncology research. Samples of canine mammary carcinomas were taken for cell culture and 2 cell lines were established and characterized in terms of cell morphology, tumourigenicity and global gene expression. Both cell lines presented spindle-shape morphology and shown common malignant features as in vitro invasion potential and expression of epithelial and mesenchymal proteins. Also, we found gene expression patterns between the 2 cell cultures in comparison to the normal mammary gland tissue. Cells from M25 culture showed a higher invasion and in vivo tumourigenic potential, associated to the overexpression of genes involved in focal adhesion and extracellular matrix communication, such as FN1, ITGA8 and THBS2. The phenotypic characterization of these cells along with their global gene expression profile potentially determine new therapeutic targets for mammary tumours.

Identification of prognostic collagen signatures and potential therapeutic stromal targets in canine mammary gland carcinoma.

Increasing evidence indicates that the tumor microenvironment plays a critical role in regulating the biologic behavior of breast cancer. In veterinary oncology, there is a need for improved prognostic markers to accurately identify dogs at risk for local and distant (metastatic) recurrence of mammary gland carcinoma and therefore would benefit from adjuvant therapy. Collagen density and fiber organization have been shown to regulate tumor progression in both mouse and human mammary tumors, with certain collagen signatures predicting poor outcomes in women with breast cancer. We hypothesized that collagen signatures in canine mammary tumor biopsies can serve as prognostic biomarkers and potential targets for treatment. We used second harmonic generation imaging to evaluate fibrillar collagen density, the presence of a tumor-stromal boundary, tumor associated collagen signatures (TACS) and individual collagen fiber characteristics (width, length and straightness) in grade I/II and grade III canine mammary tumors. Collagen density, as well as fiber width, length and straightness, were inversely correlated with patient overall survival time. Notably, grade III cases were less likely to have a tumor-stromal boundary and the lack of a boundary predicted poor outcome. Importantly, a lack of a defined tumor-stromal boundary and an increased collagen fiber width were associated with decreased survival even when tumor grade, patient stage, ovariohysterectomy status at the time of mammary tumor excision, and histologic evidence of lymphovascular invasion were considered in a multivariable model, indicating that these parameters could augment current methods to identify patients at high risk for local or metastatic progression/recurrence. Furthermore, these data, which identify for the first time, prognostic collagen biomarkers in naturally occurring mammary gland neoplasia in the dog, support the use of the dog as a translational model for tumor-stromal interactions in breast cancer.

MicroRNAs in the development and neoplasia of the mammary gland.

Study on the role of microRNAs (miRs) as regulators of gene expression through posttranscriptional gene silencing is currently gaining much interest,due to their wide involvement in different physiological processes. Understanding mammary gland development, lactation, and neoplasia in relation to miRs is essential. miR expression profiling of the mammary gland from different species in various developmental stages shows their role as critical regulators of development. miRs such as miR-126, miR-150, and miR-145 have been shown to be involved in lipid metabolism during lactation. In addition, lactogenic hormones influence miR expression as evidenced by overexpression of miR-148a in cow mammary epithelial cells, leading to enhanced lactation. Similarly, the miR-29 family modulates lactation-related gene expression by regulating DNA methylation of their promoters. Besides their role in development, lactation and involution, miRs are responsible for breast cancer development. Perturbed estrogen (E2) signaling is one of the major causes of breast cancer. Increased E2 levels cause altered expression of ERα, and ERα-miR cross-talk promotes tumour progression. miRs, such as miR-206, miR-34a, miR-17-5p, and miR-125 a/b are found to be tumour suppressors; whereas miR-21, miR-10B, and miR-155 are oncogenes.Studies using an ACI rat model showed similar findings of miR dysregulation due to excess E2, and a natural phenol antioxidant ellagic acid showed therapeutic properties by reversing the miR dysregulation. This review focuses on the recent findings concerning the role of miRs in developmental stages of the mammary gland (mainly lactation and involution stages) and their involvement in breast cancer progression. Further studies in this area will help us understand the molecular details of mammary gland biology,as well as miRs that could be therapeutic targets of breast cancer.

Neoplasia de mama en caninos y felinos atendidos en la ciudad de Aracaju-Brasil

The objective of this research was to observe the incidence of breast tumor in companion animals treated at the Dr. Vicente Borelli Veterinary Hospital in the city of Aracaju, SE during the year 2015. Data from 38 patients affected by neoplasias were evaluated. The evaluation criteria used included race, age and weight, ordering the values found and submitting the frequency analysis. After the study, it was found that there was a greater involvement of animals between zero and ten kilograms (58.1%), age from six years (80.6%) and were mainly Without Definite Race ( 35.5%), followed by poodle (32.3%), Pit Bull (12.9%), Pinscher and Dachshund (6.5%), German Shepherd and Coocker (3.2%). In the felines the high prevalence occurred with weight between zero and four kilos (57.1%), age from six years (85.7%) being Siamese the most affected race (71.4%), followed by Hair Brazilian Short (28.6%). It is concluded that senile animals independent of the species are more predisposed to acquire the disease. But dogs are affected to a greater extent. Therefore, it is essential to have a closer monitoring of older dogs and cats by the Veterinarian. Are needed other studies and research in the area of Veterinary Oncology to better understand the relevant aspects of mammary neoplasia.

Immunohistochemical Expression of P-glycoprotein and Breast Cancer Resistance Protein in Canine Mammary Hyperplasia, Neoplasia and Supporting Stroma

Immunohistochemical Expression of P-glycoprotein and Breast Cancer Resistance Protein in Canine Mammary Hyperplasia, Neoplasia and Supporting Stroma

Prevalence of Glomerulopathies in Canine Mammary Carcinoma

The incidence and prevalence of paraneoplastic glomerulopathy, especially associated with carcinoma, are a matter of debate and the causal link between cancer and glomerular diseases remains unclear. The aim of this study was to evaluate renal biopsies of selected bitches with spontaneous mammary gland carcinoma. We hypothesized that dogs with mammary carcinomas would show histologic evidence of glomerular pathology. A prospective study was performed in dogs with naturally occurring mammary carcinoma that were undergoing tumor resection and ovariohysterectomy. We evaluated renal biopsies of 32 bitches with spontaneous mammary gland carcinoma and 11 control dogs without mammary gland neoplasia. Samples were obtained from the left kidney and the biopsy material was divided for light microscopy (LM), immunofluorescence (IF) and transmission electron microscopy (TEM). Light microscopy abnormalities were identified in 78.1% of dogs with mammary carcinoma (n = 25) and in none of the dogs in the control group. Focal glomerular mesangial matrix expansion was the most common alteration (n = 15, 60.0%), but mesangial cell proliferation (n = 9, 36.0%) and focal segmental glomerulosclerosis (n = 9, 36.0%), synechiae (n = 7, 28.0%), and globally sclerotic glomeruli (n = 6, 24.0%) were also frequent in dogs with malignancy. Immunofluorescence microscopy revealed strong IgM staining was demonstrated in 64.3% (n = 18) of carcinoma dogs. Transmission electron microscopy from dogs with carcinoma revealed slight changes, the most frequent of which was faint sub-endothelial and mesangial deposits of electron-dense material (78%). Mesangial cell interpositioning and segmental effacement of podocyte foot processes were identified in some specimens (45%). Changes in the glomerulus and proteinuria are common in dogs with naturally occurring mammary carcinoma and this condition appears to provide an excellent large animal model for cancer-associated glomerulopathy in humans.

Immunostaining of micrometastases of spontaneous mammary neoplasias of bitches in lymph nodes through receptor CD44

The CD44 is an adhesion molecule, which belongs to the multifunctional family of transmembrane glycoproteins and is closely related to tumor progression. The aim of this study was to evaluate the immunostaining for CD44 in malignant mammary neoplasia of female dogs, with and without metastasis at the regional lymph nodes, assign it as a prognostic factor in early detection of metastases; relate it with the immunostaining for MMP-9, e-cadherin and VEGF. The experimental groups were: dogs with mammary tumor, with (Group M) or without metastasis (Group N) detectable in lymph nodes. The mammary tumors were classified according to the World Health Organization. The technique of immunohistochemistry was used in paraffin-embedded samples. To determine the percentage of immunostaining was considered only the neoplastic epithelial cells. For the CD44 antibody was used the immunostaining on T lymphocytes in lymph nodes of both groups. The immunostaining on T lymphocytes were higher in group N and lower in group M. There was significant increase in CD44 immunostaining in the site of the primary tumor (neoplastic epithelial cells) for metastasis, as well as the staining of MMP-9 and E-cadherin. It was concluded that CD44 may act together with other molecules, such as MMP-9 and E-cadherin. It is proposed that early detection of micrometastasis is made on T lymphocytes in lymph nodes draining malignant mammary neoplasms in female dogs.

Immunohistochemical Expression of P-glycoprotein and Breast Cancer Resistance Protein in Canine Mammary Hyperplasia, Neoplasia and Supporting Stroma

The ability of a tumour to become simultaneously resistant to different drugs is known as multidrug resistance and is often due to the expression of ATP-dependent binding cassette transporters (ABC-transporters) such as P-glycoprotein (PGP) and breast cancer resistance protein (BCRP). In this study, the expression of PGP and BCRP was determined in the components of hyperplastic and neoplastic canine mammary glands, including the supporting stroma. The variation of expression of these molecules in carcinomas was evaluated between lesions of different histological stage and grade of malignancy. Samples included 47 hyperplastic tissues and 10 benign and 46 malignant neoplasms. Tumours were classified into histological subtype, histological stage and grade. Immunohistochemical evaluation of PGP and BCRP expression showed that both markers are potentially expressed by epithelial cells, myoepithelial cells in complex tumours and mesenchymal cells in mixed tumours, but expression of both proteins was significantly higher in malignant epithelial cells versus hyperplastic epithelium or the epithelium of benign tumours. BCRP showed significantly higher expression in epithelial cells of simple carcinomas versus those of complex and mixed carcinomas. Grade II and III carcinomas had higher epithelial PGP expression than grade I tumours. The positivity of stromal fibroblasts was higher in histological stage II versus I carcinomas, and in histological grade II versus I carcinomas. Malignant and invasive tumours were more likely to express PGP and/or BCRP in luminal and stromal components and evaluation of these markers could provide valuable information for the identification of tumours characterized by an aggressive and chemoresistant phenotype.

Abstract 175: Transcriptomic and epigenetic dynamics of breast cancer progression in the MMTV-PyMT mouse model

Abstract Using RNA-sequencing and ERRBS (enhanced reduced representation bisulphite sequencing), we identified genes involved in breast cancer malignant progression. Human breast cancers have complex molecular mechanisms of progression and metastasis. To improve diagnosis and drug development, it is critical to identify the genes and molecular pathways involved in tumor progression and malignant transition. Using the polyoma middle T antigen (PyMT) mouse model, we profiled gene expression from four different stages of tumor progression, including hyperplasia, adenoma/MIN (mammary intraepithelial neoplasia), early and late carcinoma. We identified a large number of differentially expressed genes in tumors compared with normal mammary gland, enriched in E2F targets and G2M checkpoint genes. Using the temporal information, we found Myc, Sox4 and Casp9 were associated with tumor progression. Using co-expression network analysis, we identified signature modules of panels of genes, revealing novel insights into molecular mechanisms of breast tumorigenesis. For example, Mcm6 and Ncapd2, hub genes in a DNA replication and cell cycle module, predict metastasis in human samples. We also found the Hells, Hmgb2 and Cit genes to be increased in expression in both mouse and human TCGA (The Cancer Genome Atlas) datasets. We complemented these studies by profiling DNA methylation using ERRBS in the same samples. We identified a large number of differentially methylated cytosines (DMCs), enriched in cis-regulatory elements as well as near genes in cancer-related pathways. A small subset of the DMCs was well conserved between the progressive stages of tumorigenesis, with the greatest shift occurring with the transition to malignancy. We also observed a global hypomethylation and a shift towards a subset of loci with hypermethylation with tumor progression. Expression of some tricarboxylic acid (TCA) cycle genes was negatively correlated with DNA methylation, which may reflect altered metabolic regulation in carcinoma. We then constructed a co-methylation network and discovered a module with decreased DNA methylation in tumor that was enriched with genes from WNT and MAPK signaling pathways. In addition, we compared our results to the human TCGA breast carcinoma dataset and found the epigenetic modules to be overall distinctive between the two species. Altogether, our gene expression, DNA methylation and network analyses with the PyMT mouse model shed new light on transcriptional and epigenetic dynamics during breast cancer malignant progression and reveal gene modules that may regulate this biological process. Citation Format: Ying Cai, Ruben Nogales-Cadenas, Quanwei Zhang, Jhih-rong Lin, Wen Zhang, Zhengdong Zhang. Transcriptomic and epigenetic dynamics of breast cancer progression in the MMTV-PyMT mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 175.

A review of medically unnecessary surgeries in dogs and cats

JAVMA • Vol 248 • No. 2 • January 15, 2016 In ancient Rome, during the First Century CE, Lucius Columella wrote that it was proper to remove the tails of puppies to prevent their growth to an “abominable length” and to prevent madness, which is presumed to refer to rabies.1 Although the idea that this procedure could protect dogs against rabies has long since been abandoned, tail docking is still commonly performed, both because of a belief that it reduces the incidence of injuries and because of the resulting perceived improvements in aesthetics. However, the effectiveness of this procedure in preventing injuries has been questioned, and the idea of performing this and other surgical procedures on animals solely for cosmetic reasons has been heavily criticized in many parts of the world.2 In fact, some countries have passed legislation restricting these types of surgeries. While anecdotal reports suggest that certain cosmetic procedures such as ear cropping are in decline in North America, to our knowledge there are no reliable estimates on the numbers of these procedures performed annually. Most surgical procedures performed on dogs and cats in North America are performed for therapeutic, diagnostic, or preventive purposes; that is, they are medically necessary. In contrast, procedures that are not necessary for maintaining health or that are not beneficial to the animal can be classified as MUSs. This would include procedures performed mainly to alter the appearance of animals (eg, ear cropping and tail docking in dogs), procedures performed solely to prevent behaviors that are destructive or annoying (eg, devocalization and defanging in dogs and onychectomy in cats), and procedures of dubious or minimal benefit (eg, dewclaw removal in dogs). Note that elective neutering of healthy dogs and cats has historically been performed to prevent or reduce the risk of future health problems (eg, pyometra, mammary gland neoplasia, and reproductive tract–related neoplasia) and to prevent unplanned breeding, which benefits the population as a whole by reducing the number of unwanted animals.3 Thus, for the purposes of the A review of medically unnecessary surgeries in dogs and cats

Avaliação dos marcadores de prognóstico Ki-67, p53 no tumor mamário maligno de cadelas

In view of the high incidence of mammary neoplasia in dogs, the aim of this study was to investigate the prognostic markers in the malignant mammary tumors of the female dog. For this, a sample of 30 mammary tumors was selected. The samples were divided into three groups according to histopathological classification: carcinosarcoma, solid carcinoma or tubulopapillary carcinoma. The Ki-67, p53, prognostic markers were evaluated by means of immunohistochemistry, using the streptavidin-biotin-peroxidase technique. For Ki-67, a significant difference was seen between solid and tubulopapillary carcinomas. The p53, a significant difference was seen between carcinosarcoma and solid anda tubulopapillary carcinomas.

Avaliação da concentração expirada de isoflurano em infusão continua de remifentanil em cadelas submetidas a mastectomia

<p>The aims of this study were to evaluate the effects of two constant rate infusions of remifentanil on end tidal isoflurane (ETiso) in dogs undergoing mastectomy surgery. Eighteen bitches, 12<span style="text-decoration: underline;">+</span>2 years of age, weighing 15<span style="text-decoration: underline;">+</span>5 Kg were randomized into 3 groups (n=6/group) and underwent unilateral mastectomy due to mammary neoplasia. All animals received the premedications of morphine (0.5 mg Kg-1) and acepromazine (0.03 mg Kg-1) by intramuscular route (IM). Propofol dose-effect was used for induction of anesthesia. The animals were intubated and connected to a circle breathing system, and IPPV (intermittent positive pressure ventilation) was used to maintain normocapnia with an oxygen flow rate of 2 L/min and FiO2 100%. Anesthesia was maintained with isoflurane and saline solution (control group [GCON], n=6) or intravenous infusion of remifentanil at a rate of 0.15 ?g Kg-1min-1 (REMI 0.15 n=6) or 0.3 ?g Kg-1min-1 (REMI 0.3 n=6). Cardiopulmonary variables and ETiso were monitored before and every 15 minutes after the start of surgery. The data were analyzed by ANOVA with multiple repetitions between moments and ANOVA followed by the Student Newman Keuls test (p£0.05) for comparisons between groups. Heart rate was lower at all moments in the REMI 0.15 and REMI 0.3 groups than in the GCON, and heart rate was not significantly different between the two remifentanil infusion groups. Additionally, the arterial blood pressure values (SAP, MAP and DAP) were not different between all groups. Baseline values (before surgery) of ETiso were not different between the 3 groups. After the start of surgery, ETiso ranged from 1.37±0.3 to 1.05±0.19 in the control group; in the REMI 0.15 and REMI 0.3 groups, ETiso was 36.5% and 65.7% lower than in the control group (M15). Remifentanil infusion reduced ETiso in a dose-dependent manner in animals undergoing radical mastectomy without causing significant cardiopulmonary alterations.</p>

Avaliação da concentração expirada de isoflurano em infusão continua de remifentanil em cadelas submetidas a mastectomia

<p>The aims of this study were to evaluate the effects of two constant rate infusions of remifentanil on end tidal isoflurane (ETiso) in dogs undergoing mastectomy surgery. Eighteen bitches, 12<span style="text-decoration: underline;">+</span>2 years of age, weighing 15<span style="text-decoration: underline;">+</span>5 Kg were randomized into 3 groups (n=6/group) and underwent unilateral mastectomy due to mammary neoplasia. All animals received the premedications of morphine (0.5 mg Kg-1) and acepromazine (0.03 mg Kg-1) by intramuscular route (IM). Propofol dose-effect was used for induction of anesthesia. The animals were intubated and connected to a circle breathing system, and IPPV (intermittent positive pressure ventilation) was used to maintain normocapnia with an oxygen flow rate of 2 L/min and FiO2 100%. Anesthesia was maintained with isoflurane and saline solution (control group [GCON], n=6) or intravenous infusion of remifentanil at a rate of 0.15 ?g Kg-1min-1 (REMI 0.15 n=6) or 0.3 ?g Kg-1min-1 (REMI 0.3 n=6). Cardiopulmonary variables and ETiso were monitored before and every 15 minutes after the start of surgery. The data were analyzed by ANOVA with multiple repetitions between moments and ANOVA followed by the Student Newman Keuls test (p£0.05) for comparisons between groups. Heart rate was lower at all moments in the REMI 0.15 and REMI 0.3 groups than in the GCON, and heart rate was not significantly different between the two remifentanil infusion groups. Additionally, the arterial blood pressure values (SAP, MAP and DAP) were not different between all groups. Baseline values (before surgery) of ETiso were not different between the 3 groups. After the start of surgery, ETiso ranged from 1.37±0.3 to 1.05±0.19 in the control group; in the REMI 0.15 and REMI 0.3 groups, ETiso was 36.5% and 65.7% lower than in the control group (M15). Remifentanil infusion reduced ETiso in a dose-dependent manner in animals undergoing radical mastectomy without causing significant cardiopulmonary alterations.</p>

The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis.

The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance when studying the subtypes of epithelial breast carcinoma, which are categorized according to their expression of luminal or basal markers. The epithelial mesenchymal transition (EMT) is a pivotal event in tumor invasion. It is important to understand mechanisms that regulate this process, which bears relation to the normal dynamic of epithelial/basal phenotype regulation in the mammary gland. Understanding this process could provide answers for the regulation of EMT in breast cancer, and thereby identify potential targets for therapy. Evidence points towards a role for hedgehog signaling in breast tissue homeostasis and also in mammary neoplasia. This review examines our current understanding of role of the hedgehog-signaling (Hh) pathway in breast epithelial cells both during breast development and homeostasis and to assess the potential misappropriation of Hh signals in breast neoplasia, cancer stem cells and tumor metastasis via EMT.

Correlation of In Vivo and Ex Vivo ADC and T2 of In Situ and Invasive Murine Mammary Cancers.

Ex vivo MRI may aid in the evaluation of surgical specimens, and provide valuable information regarding the micro-anatomy of mammary/breast cancer. The use of ex vivo MRI to study mouse mammary cancer would be enhanced if there is a strong correlation between parameters derived from in vivo and ex vivo scans. Here, we report the correlation between apparent diffusion coefficient (ADC) and T2 values measured in vivo and ex vivo in mouse mammary glands with in situ cancers (mammary intraepithelial neoplasia (MIN)) and invasive cancers (those which spread outside the ducts into surrounding tissue). MRI experiments were performed on the Polyoma middle T oncoprotein breast cancer mouse model (n = 15) in a 9.4T scanner. For in vivo experiments, T2-weighted (T2W) images were acquired to identify abnormal regions, then ADC and T2 values were measured for nine selected slices. For ex vivo experiments, a midline incision was made along the spine, and then skin, glands, and tumors were gently peeled from the body. Tissue was fixed in formalin, placed around a mouse-sized sponge, and sutured together mimicking the geometry of the gland when attached to the mouse. The same pulse sequences used for in vivo experiments were repeated for ex vivo scans at room temperature. Regions of interest were manually traced on T2W images defining features that could be identified on in vivo and ex vivo images. The results demonstrate a strong positive correlations between in vivo and ex vivo invasive cancers for ADC (r = 0.89, p <0.0001) and T2 (r = 0.89, p <0.0001) values; and weak to moderate positive correlations between in vivo and ex vivo in situ cancers for ADC (r = 0.61, p <0.0001) and T2 (r = 0.79, p <0.0001) values. The average ex vivo ADC value was about 54% of the in vivo value; and the average ex vivo T2 was similar to the in vivo value for cancers. Although motion, fixation, and temperature differences affect ADC and T2, these results show a reliable relationship between ADC and T2 in vivo and ex vivo. As a result ex vivo images can provide valuable information with clinical and research applications.

The chemokine receptor CCR6 facilitates the onset of mammary neoplasia in the MMTV-PyMT mouse model via recruitment of tumor-promoting macrophages.

BackgroundThe expression of the chemokine receptor CCR6 has been previously correlated with higher grades and stages of breast cancer and decreased relapse-free survival. Also, its cognate chemokine ligand CCL20 has been reported to induce proliferation of cultured human breast epithelial cells.MethodsTo establish if CCR6 plays a functional role in mammary tumorigenesis, a bigenic MMTV-PyMT CCR6-null mouse was generated and mammary tumor development was assessed. Levels of tumor-infiltrating immune cells within tumor-bearing mammary glands from MMTV-PyMT Ccr6WT and Ccr6−/− mice were also analyzed.ResultsDeletion of CCR6 delayed tumor onset, significantly reduced the extent of initial hyperplastic outgrowth, and decreased tumor incidence in PyMT transgenic mice. CCR6 was then shown to promote the recruitment of pro-tumorigenic macrophages to the tumor site, facilitating the onset of neoplasia.ConclusionsThis study delineated for the first time a role for CCR6 in the development of breast cancer, and demonstrated a critical function for this receptor in maintaining the pro-tumorigenic cancer microenvironment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0394-1) contains supplementary material, which is available to authorized users.

The Journal of Mammary Gland Biology and Neoplasia into the future - the potential of plasticity and pluripotency.

It is fair to say that perhaps one of the most fascinating concepts for those studying the mammary gland, the milk it produces, and the cancer it succumbs to, is the potential diversity harbored within the organ. As a tissue, the gland is plastic in that it evolves from being a highly-proliferative structure derived from pluripotent stem cells to a terminally-differentiated organ capable of secreting large amounts of milk with a complex and unique composition. In turn, this milk in all its different forms is the basis for the survival of all mammals as well as for a global dairy industry. Yet as an organ is also susceptible to a cancer that is complex and dangerous, and that affects the lives of many women across the world. Similar to the organ we study, the opportunity is present for our Journal to demonstrate its plasticity and pluripotency. Almost 20 years ago the Journal of Mammary Gland Biology and Neoplasia went to print under the editorial supervision of Peggy Neville and Dan Medina in response to a call from members of the former International Committee on Mammary Gland Biology for a publication to serve the field. As introduced by them in January 1996, the Journal was created specifically with the goal of publishing quarterly issues comprised of minireviews Bto meet the needs of researchers within and outside the field of mammary gland biology for an integrated source of information derived from studies of the development, function and pathology of the mammary gland^ [1]. That first issue was entitled BExperimental models of development, function, and neoplasia^ (Guest Edited by Dan Medina and Charles Daniel) and had contributions with titles ranging from BRole of mesenchymal-epithelial interactions in mammary gland development^ [2], to BGenetic manipulation of mammary epithelium by transplantation^ (REF [3]). These and the other titles from that issue have gone on to become seminal reviews of topics that have now formed the mainstay for much of the research that has been undertaken over the past 20 years to enhance our understanding of mammary gland biology, lactation physiology, and breast cancer. At the time of the Journal’s inception, there was no equivalent publication for the burgeoning field that boasted a solid and diverse base of investigators stemming from a long-standing connection between the fields of dairy science and breast cancer research. Relative to the current day, the funding climate of the day was unquestionably generous. Around that time there was also a massive expansion of accompanying disciplines, in particular through the development of readily-accessible tools for the study of molecular and developmental biology. Across the course of the past 20 years the Journal has continued to serve as a mainstay for our community of dedicated scientists by publishing a fascinating breadth of topics that has evolved with the latest methods and discoveries. What has remained absent all these years, however, is a place for the primary literature in the field of mammary gland biology to be published. Of course, all authors inherently aspire to publish their works in the renowned top-tier Bhigh impact factor^ journals. Yet, these venues are often unreceptive to many of the topics published by investigators in our field. Authors have typically had to seek out publication homes for their work in a range of * Russell C. Hovey rchovey@ucdavis.edu