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Serum HER2 levels are increased in cats with mammary carcinomas and predict tissue HER2 status

Serum HER2 levels are increased in cats with mammary carcinomas and predict tissue HER2 status

In order to validate the measurement of sHER2 levels by the Dot blot assay, the antigenic specificity of the anti-HER2 monoclonal antibody (clone SP3) was evaluated through western blot analysis. As expected, the SP3 antibody recognizes a protein band of ~185 kDa corresponding to predicted molecular weight of full-length HER2 in whole cell extracts of both human breast cancer cells (SKBR3, Figure 4A, line 1) and feline mammary tumor cells (FMCp, Figure 4A, lane 2), and cross-reacts with the recombinant human HER2-ECD (Figure 4A, lane 3, 84-90 kDa). Further western blot analysis revealed that the anti-HER2 monoclonal antibody detected several protein bands with masses ranging from 120 to 140 kDa in the serum samples from cats diagnosed with MC overexpressing HER2 (Figure 4A, lanes 4 and 5), suggesting that proteolytic cleavage of HER2 occurs at the intracellular domain (ICD), leading to the production of truncated HER2 soluble forms which are quantifiable by the Dot blot assay (Figure 4B). As mentioned above, cats diagnosed with HER2-overexpressing MC (scored as 2+ and 3+), showed significantly (p = 0.03) higher sHER2 levels (Figure 4B, lines 5 and 6) than cats with HER2- negative mammary carcinomas (Figure 4B, lines 3 and 4) or healthy cats (Figure 4B, line 2).
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Expression of matrix metalloproteinase 2 (MMP-2), E-cadherin and Ki-67 in metastatic and non-metastatic canine mammary carcinomas

Expression of matrix metalloproteinase 2 (MMP-2), E-cadherin and Ki-67 in metastatic and non-metastatic canine mammary carcinomas

mammary carcinomas in women and found that MMP-2 plays an important part in the metastasis of those tumours to regional lymph nodes. In addition, the authors found a significantly higher MMP-2 expression in the metastasis (lymph node) than in the primary tumour. An increased MMP-2 and MMP-9 expression was found in a number of tumours in humans. It is most often associated with un- favorable prognostic factors, such as the clinical advance- ment of the disease, an infiltration to the surrounding tissues, lymph node metastases and a shortened disease- free survival [29–35]. However, not all studies associate increased expressions of MMP-9 and MMP-2 in the tumour tissue with a poor prognosis. For example, there was a positive correlation between the presence of macro- phages expressing high levels of MMP-9 in colorectal can- cer and a decreased number of metastases [36]. Similarly, Zhang et al. [37] analysed close to 100 cases of invasive breast cancer in women and found no correlation between high expression of MMP-9 and adverse prognostic factors.
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Atm heterozygous deficiency enhances development of mammary carcinomas in p53heterozygous knockout mice

Atm heterozygous deficiency enhances development of mammary carcinomas in p53heterozygous knockout mice

the homozygous loss of the p53 allele was a necessary condition for the development of mammary carcinomas, whereas the Atm null allele exhibited haploinsufficiency. Haploinsufficiency for tumour development was reported for the Nbn knockout mice, the mouse homologue of NBS1. Heterozygosity for the Nbn knockout allele ren- dered the mice susceptible to tumour development, yet the Nbn wild-type allele was fully retained in all 12 tumours examined [29]. p27 heterozygotes are also predisposed to tumours in multiple tissues when challenged with irradia- tion or a chemical carcinogen, and in the developed tumours the remaining wild-type allele is neither mutated nor silenced, indicating that p27 is haploinsufficient for tumour suppression [30]. In that study, heterozygous Atm knockout enhanced mammary carcinoma development in p53-heterozygous deficient mice, but the effect of Atm defi- ciency was not as profound. A previous study showed that heterozygosity for the Atm knockout allele did not enhance tumour development but that dominant-negative type mis- sense mutations in the Atm gene did [14]. In humans, het- erozygosity of the truncation-type mutations, which represent the majority of Atm mutations that occur in humans, had no effect on carcinogenesis, suggesting that enhancement in tumourigenesis depends strongly on muta- tion type. However, in the present study we demonstrated
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T-cell epitope strength in WAP-T mouse mammary carcinomas is an important determinant in PD1/PD-L1 immune checkpoint blockade therapy

T-cell epitope strength in WAP-T mouse mammary carcinomas is an important determinant in PD1/PD-L1 immune checkpoint blockade therapy

Using the SV40 transgenic WAP-T/WAP-T NP mouse models for mammary carcinomas, we compared the response to immune checkpoint blockade therapy in tumor mice expressing either SV40 T-antigen containing the LCMV NP-epitope (T-Ag NP in WAP-T NP mice), or the unmodified T-antigen (T-Ag in WAP-T mice). Specifically, we asked, whether the presence of the highly immunogenic NP-epitope in T-Ag NP influences this response in comparison to the weakly immunogenic T-cell epitopes of T-Ag in WAP-T tumor mice. Treatment of WAP-T NP tumor mice with either anti-PD1 or anti-PD-L1 antibodies led to tumor regression, with anti-PD-L1 treatment being more effective. However, tumors had fully re-appeared after 21 days, indicating that CTL exhaustion had been rapidly re-established. Surprisingly, the same treatment applied to WAP-T tumor mice resulted in a significantly prolonged period of tumor regression. We provide evidence that in contrast to the weak antigenic stimuli exerted by T-cell epitopes of T-Ag, the strong antigenic stimulus of the NP-epitope in T-Ag NP has a dual effect: (i) a rapid generation of active NP-specific CTLs, accompanied (ii) by accelerated CTL exhaustion. Our data support the hypothesis that the immunogenicity of tumor antigen T-cell epitopes strongly influences the success of immune checkpoint blockade therapy.
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Immunoexpression of Cathepsin D and S100A4 Protein and Their Molecular Subtyptes in Canine Mammary Carcinomas

Immunoexpression of Cathepsin D and S100A4 Protein and Their Molecular Subtyptes in Canine Mammary Carcinomas

Cathepsin D (CD), a lysosomal protease, and S100A4 protein, a calcium binding motif, are considered to be involved in metastasis in various human cancers. No data regarding such proteins are available for canine mammary carcinomas (CMCs). Accordingly, their expression in association with known factors of prognosis was investigated in this study. For that, 66 surgically resected CMCs were submitted to an immunohistochemical evaluation using anti CD, S100A4 protein, HER2, estrogen receptor α, cytokeratin 5, and p63 antibodies, further characterizing the tumors’ molecular subtype. An increase in S100A4 immunoexpression by neoplastic luminal mammary cells was associated with an infil- trative tumor mode of growth, consequently leading us to conclude that S100A4 protein could be related to progression in CMCs. Additionally, the occurrence of the luminal A molecular subtype was associated with the complex histotype in CMCs. Although we have demonstrated that changes in S100A4 protein immunoexpression occurs in CMCs, further studies are needed to determine whether this represents important independent biomarkers for CMCs.
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Metastasis is an early event in mouse mammary carcinomas and is associated with cells bearing stem cell markers

Metastasis is an early event in mouse mammary carcinomas and is associated with cells bearing stem cell markers

We next examined single cell suspensions prepared from the lungs of MMT mice at different stages of mammary cancer progression. Our hypothesis was, if CD44 + and Sca1 + cells are involved in metastasis to the lung from primary mammary carcinomas, we should be able to find such cells in the lungs. Single cell suspen- sions obtained from the lungs of MMT mice at increas- ing ages were therefore stained with monclonal antibodies against CD44, Sca1 or MUC1 and examined under microscopy. Primary mammary tumor cells from MMT mice were used as positive control in the left panels of Figure 2b. Red-stained CD44, Sca1, or MUC1- positive cells were identified among the lung tissue cells prepared from MMT mice at each age group, although an age-dependent increase in cells expressing each of these markers was observed (Figure 2c). Comparable numbers of CD44 + or Sca1 + cells were observed in each age group between MT and MMT mice, suggesting that the expression of MUC1 does not affect the pool of CD44 + or Sca1 + cells (Figure 2c). In addition, the major- ity of the CD44/Sca1 + lung cells also expressed the sur- face markers CD24, ESA, or estrogen receptor (ER) at levels comparable with those expressed by primary tumor cells (Figures 2d and 2e). These experiments indi- cate that cells bearing stem cell, tumor or mammary epithelial markers can be identified in the lungs of MMT mice, suggesting that they originate from
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Characterisation of fibrosis in chemically-induced rat mammary carcinomas using multi-modal endogenous contrast MRI on a 1.5T clinical platform

Characterisation of fibrosis in chemically-induced rat mammary carcinomas using multi-modal endogenous contrast MRI on a 1.5T clinical platform

In this study, a range of endogenous MR imaging contrasts were measured in chemically-induced mammary carcinomas arising in rats injected with MNU; the tumours were highly heterogeneous and presented with a range of fibrosis levels as previously observed in this model and typical of the clinical setting [18, 34]. The imaging performed in the study used exclusively clinical hardware, conferring greater translational relevance to the study, and the scanning was performed within a clinical timeframe using standard and prototype (UTE and DWI) sequences developed by the manufacturer for use on the clinical platform. It has previously been shown that this platform is suitable for preclinical work of this nature [21, 35], and can return functional MR parameters with good measurement repeatability across several imaging biomarkers. Repeated analysis by independent observers showed excellent repeatability of ROI positioning and all derived MR parameters except the pseudo-diffusion parameters from the IVIM diffusion model.
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Snai 1 and Epithelial Mesenchymal  Transition Related Protein  Immunoexpression in Canine  Mammary Carcinomas

Snai 1 and Epithelial Mesenchymal Transition Related Protein Immunoexpression in Canine Mammary Carcinomas

Epithelial-mesenchymal transition (EMT) is defined as switching of polarized epithelial cells to a migratory fibroblastoid phenotype. EMT is known to be involved in the progression and metasta- sis of various cancers in humans, but this specific process is still little explored in the veterinary literature. The aim of this research was to evaluate the expression of EMT-related proteins in ca- nine mammary carcinomas (CMCs). The expression of six EMT-related proteins in 94 CMCs of fe- male dogs was evaluated by immunohistochemistry using a tissue array method. Additionally, cli- nicopathological characteristics were compared with the expression of EMT-related proteins. Loss of epithelial protein and/or acquisition of the expression of mesenchymal proteins were observed in CMCs. Loss of epithelial protein and/or acquisition of the expression of mesenchymal proteins were observed, particularly in tumors with evidence of stromal invasion; however, significance was only observed between the S100A4 and vascular invasion. In addition, Snai-1 nuclear immu- noexpression was significantly related to E-cadherin loss. In conclusion, loss of epithelial proteins and/or the acquisition of mesenchymal proteins are associated with EMT and may have an impor- tant role in the evaluation of CMC patients. The unique immunoexpression pattern of Snai-1 could help to distinguish between an adenoma and a non-metastatic carcinoma and seems to be related
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Chemopreventive effects of celecoxib are limited to hormonally responsive mammary carcinomas in the neu induced retroviral rat model

Chemopreventive effects of celecoxib are limited to hormonally responsive mammary carcinomas in the neu induced retroviral rat model

In the neu-induced rat mammary carcinogenesis model, approximately 50% of mammary carcinomas in the intact model are hormonally responsive and can therefore be pre- vented by tamoxifen (2 mg/kg diet) treatment. In two inde- pendent experiments using the intact model, the average number of mammary carcinomas developing per rat following tamoxifen treatment was decreased by 49% (P < 0.0001, Table 1 and Figure 1a) and by 33% (P = 0.1, Table 1 and Fig- ure 1c), respectively. While the latter result did not reach sta- tistical significance, there was a clear trend toward decreased tumor multiplicity throughout the course of the prevention experiment. In the ovariectomized model, where tumors are hormonally nonresponsive, tamoxifen treatment had no signifi- cant effect on tumor multiplicity compared with the control groups (Table 1 and Figure 1b,d).
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Spontaneous Mammary Carcinomas in Female Dogs: Association between Immunohistochemical Degrees of Neoplasia Aggressiveness and Residual Pyrethroids

Spontaneous Mammary Carcinomas in Female Dogs: Association between Immunohistochemical Degrees of Neoplasia Aggressiveness and Residual Pyrethroids

Of the tumors diagnosed in the female dogs have the highest mammary neoplasias incidence. These neoplasias can be influenced by environmental contaminants. Despite evidence of pyrethroid toxicity, carcinogenic potential has not yet been sufficiently elucidated, there is a need to investigate their involvement in mammary tumor. In previous studies, pyrethroid residues were detected in female dogs with mammary neoplasia, however was not investigate the influence of this insecticide in the genesis and aggressiveness of mammary cancer. This study aimed to investigate possible rela- tions between pyrethroid residues and aggressiveness of mammary carcinoma in female dogs. Fifty selected female dogs were divided into five groups of 10 animals each: the Control group, female dogs without mammary neoplasia; the groups Luminal A, Luminal B, HER-2 Superexpression and Basal were constituted by female dogs that presented in- guinal mammary carcinoma classified immunohistochemically. The aggressiveness of carcinomas was evaluated by immunohistochemistry (HER-2, p63, estrogen receptor). Residual concentrations of the pyrethroids from the mammary gland and fat tissue adjacent to it were determined by HPLC. Data were analyzed by Chi-Square test. Of the all animals, six presented residues of pyrethroids in mammary samples and 10 presented it in fat tissue samples. There was no sta- tistical evidence that pyrethroids are involved in mammary carcinoma aggressiveness in female dogs.
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Spontaneous Mammary Carcinomas in Female Dogs: Association between the Immunohistochemical Degree of Aggressiveness of Tumors, Intensity of DNA Damage and Residues of Pyrethroids

Spontaneous Mammary Carcinomas in Female Dogs: Association between the Immunohistochemical Degree of Aggressiveness of Tumors, Intensity of DNA Damage and Residues of Pyrethroids

Detection of DNA damage was performed using the Comet Assay performed on cells harvested by citopunc- ture of mammary tumors surgically excised (Groups I and II) and 11 fragments of biopsied breast of animals in Group III. The test was conducted in accordance with the methodologies previously described [13] with modifica- tions and all steps were performed under indirect light. After harvesting the cells of the breast tissue, they were suspended in PBS free of Ca 2+ and Mg 2+ in cold and in

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Prolactin induced mouse mammary carcinomas model estrogen resistant luminal breast cancer

Prolactin induced mouse mammary carcinomas model estrogen resistant luminal breast cancer

Activity of the NRL-PRL promoter is not altered by estrogen [15], enabling us to examine the role of this steroid in the disease process. Proliferation of both mor- phologically normal MECs and preneoplastic epithelial hyperplasias in NRL-PRL females is very sensitive to ovariectomy (ovx) and supplemental estrogen [17,54]. In order to examine estrogen responsiveness in established carcinomas, NRL-PRL females bearing primary mam- mary adenocarcinomas were subjected to sham surgery or ovx. At the time of surgery, a biopsy was removed for examination of tumor histology, rate of proliferation, and steroid hormone receptor expression. The growth of the remaining tumors was monitored until they reached 1.5 cm in diameter (15.3 ± 8.5 days; mean ± s.d.), as described in the Materials and methods. Like the tumors in Figure 1, histotypes in this experimental panel were diverse, and ER a /PR expression varied widely. They exhibited highly variable rates of growth (Figure 6b); rates of proliferation of ER a - tumors prior to the surgery tended to be higher than ER a + tumors (P = 0.07). However, ovx did not alter rates of prolifera- tion of either ER a + or ER a - tumor cells. Consistently, ovx followed by administration of E2 failed to alter pro- liferation of an independent set of primary tumors (PCNA staining: 30.1% ± 12 vs 31.19% ± 7.9, mean ± s.d., P > 0.05, N = 5).
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STAT1 deficient mice spontaneously develop estrogen receptor α positive luminal mammary carcinomas

STAT1 deficient mice spontaneously develop estrogen receptor α positive luminal mammary carcinomas

The authors thank Drs. Paul Allen, Barry Sleckman, Emil Unanue, Ravi Uppaluri, Matthew Vesely (Washington University School of Medicine), Mark Smyth (Peter McCallum Cancer Centre), and Michel Aguet (Swiss Institute for Experimental Cancer Research) for critical review of the manuscript. The authors are grateful to Dr. Charles M Perou (University of North Carolina at Chapel Hill) for providing datasets for human breast cancers and mouse mammary tumors, Drs. David Wang and Kathie Mihindukulasuriya (Washington University School of Medicine) for performing viral microarray analyses, and Jessica Archambault and James Michael White (Washington University School of Medicine), Katie Bell (University of California, Davis), and Wei Zhu (New York University School of Medicine) for their excellent technical assistance. This work was supported by a Susan G Komen Foundation Postdoctoral Fellowship Award (SRC), a Finnel Family Fund Grant from the Cancer Research Institute (RDS), and grants from the National Cancer Institute (MJW, RDC, and RDS), National Institute of Allergy and Infectious Diseases (DEL), the Ludwig Institute for Cancer Research (RDS), and Fondazione Beretta (Brescia, Italy) (WV).
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Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse

Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse

Our results apply primarily to ductal mammary carcinomas that are represented in vitro by MCF7 and HCC1419 cells derived from estrogen receptor–positive ductal carcinomas of the luminal subtype (57). However, only 50% of the lobular mammary carcinomas fol- lowed this pattern of tumor spreading. baicalein-insensitive CCIDs were formed by MDA-Mb321 and HCC1443 mammary carcinoma cells that are derived from estrogen receptor–negative ductal carci- nomas of the basal subtype and lack ALOxs. This is in contrast to our findings in human tumors and could be due to changes induced by in vitro culturing. Furthermore, the CCID assay suggested that tumors derived from other organs apparently use LOx-independent mechanisms. These include most colorectal carcinomas, melano- mas, and a pancreatic cancer. Thus, there is no universal mechanism by which different types of tumors form and propagate lymph node metastases. They apparently also have at their disposal ALOx15- independent mechanisms to enter lymphatic vessels and do not use bulk but rather single-cell invasion, with or without epithelial- mesenchymal transition, possibly depending on TGF-β (24).
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The premenstrual syndrome, premenstrual mastodynia, fibrocystic mastopathy and infertility have often common roots: effects of extracts of chasteberry (Vitex agnus castus) as a solution

The premenstrual syndrome, premenstrual mastodynia, fibrocystic mastopathy and infertility have often common roots: effects of extracts of chasteberry (Vitex agnus castus) as a solution

Fibrocystic mastopathy is the most common mam- mary pathology and affects 60–80% of women in the reproductive age [32–34]. Many women are frightened that the development of fibrous nodes and/or cysts indicates malignity and there is evidence that the in- cidence of mammary cancers is indeed higher in women with fibrocystic mastopathy [35]. These fibro- cystic phenomena increase mammographic breast density which represents a risk for the development of mammary carcinomas (for review s.36). The eti- ology of FCM is not totally clear: Estrogens and pro- gestins in combination with latent hyperprolactinemia are the most commonly accused hormones which cause proliferation of mammary gland epithelia and connective tissue and which results in enlargement of ducts into cysts and proliferated connective tissue cause the nods [32]. There is also evidence that pa- tients with high mammographic density have elevated prolactin levels [36] On the other hand many patients with FCM have normal prolactin levels. A possible explanation for this phenomenon is a mutation of prolactin receptors which results in their hypersensi- tivity [37]. There is also some recently described evi- dence that such mutated prolactin receptors may be constitutively active [38]. Under these conditions a number of paracrine acting factors are locally secreted which stimulate further proliferation of surrounding cells [39]. These abnormalities seem often to be ac- companied increased local by production of proin- flammatory cytokines and/or higher susceptibility of cytokine receptors due to gene polymorphisms [39] causing local, often painful inflammatory processes and consequently high local oxidative stress. In each case, it appears from early studies that dopaminergic drugs are able to reduce both subjectively felt pain and objectively measured fibrocystic structures. The most detailed and recent information of effects of VAC preparations on FCM with or without latent hyperprolactinemia or mastodynia stem from East European studies. A brief overview of these studies is given in Table 2 and further detailed in the following text.
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Estrogenic microenvironment generated by organochlorine residues in adipose mammary tissue modulates biomarker expression in ERα positive breast carcinomas

Estrogenic microenvironment generated by organochlorine residues in adipose mammary tissue modulates biomarker expression in ERα positive breast carcinomas

The relation of diet, especially fat intake, to recognized breast cancer prognostic indicators was investigated in humans as well in animal models. In rats, a high-fat diet significantly stim- ulated tumor proliferation and cell kinetics in chemically induced mammary carcinomas [24], while in women an increase in saturated fat intake was positively associated with tumor growth and/or spread [25]. Consistent with this, our tumors from patients that reported high fat consumption exhib- ited high proliferative indices. In the present study, dairy prod- uct intake was positively correlated with tumor ERα expression. This result suggests that these dietary compo- nents could modify the tumor biological behavior, improving the response to endocrine therapy and/or survival in breast carcinoma patients.
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Estrogenic microenvironment generated by organochlorine residues in adipose mammary tissue modulates biomarker expression in ERα-positive breast carcinomas

Estrogenic microenvironment generated by organochlorine residues in adipose mammary tissue modulates biomarker expression in ERα-positive breast carcinomas

The relation of diet, especially fat intake, to recognized breast cancer prognostic indicators was investigated in humans as well in animal models. In rats, a high-fat diet significantly stim- ulated tumor proliferation and cell kinetics in chemically induced mammary carcinomas [24], while in women an increase in saturated fat intake was positively associated with tumor growth and/or spread [25]. Consistent with this, our tumors from patients that reported high fat consumption exhib- ited high proliferative indices. In the present study, dairy prod- uct intake was positively correlated with tumor ERα expression. This result suggests that these dietary compo- nents could modify the tumor biological behavior, improving the response to endocrine therapy and/or survival in breast carcinoma patients.
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Targeted activation of β catenin signaling in basal mammary epithelial cells affects mammary development and leads to hyperplasia

Targeted activation of β catenin signaling in basal mammary epithelial cells affects mammary development and leads to hyperplasia

Diverse, often invasive, lesions were observed in multiparous transgenic mice. They included squamous metaplasia presenting cutaneous epithelial lineage markers, as described by others (Miyoshi et al., 2002a; Miyoshi et al., 2002b) and invasive carcinoma composed essentially of basal (K5/K14-positive) cells. Although most human breast carcinomas express phenotypic markers suggestive of a luminal origin, cDNA microarray analysis has revealed a distinct subclass of tumors that strongly express the genes encoding basal keratins, ECM proteins, integrins and other markers of basal mammary cells (Perou et al., 2000; Sorlie et al., 2003). These tumors are associated with a poor clinical outcome. Expression of the entire set of basal cell markers by this subclass of breast tumors suggests that they may originate from mammary cell progenitors with the molecular characteristics of basal cells. The K5- ∆ N57- β cat transgenic mouse line provides a model with which to study the induction and progression of basal mammary carcinomas.
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The role and function of cadherins in the mammary gland

The role and function of cadherins in the mammary gland

osteoblasts and fi broblast-like synoviocytes helps main- tain bone and joint structures [29-31]. Little is know about where cadherin-11 is expressed normally in the mammary gland, but in several breast cancer cell lines and during mammary carcinomas, cadherin-11 becomes expressed in the epithelial cells, suggesting an EMT has occurred [32-34]. Once the carcinoma cells express cadherin-11, it provides the ability of metastatic carcinoma cells to establish themselves into the micro- environment of bone [34]. Th is is facilitated by the fact that both osteoblasts and the carcinoma cells express cadherin-11, enabling cell-cell interactions. In breast cancer cell lines, it was also demonstrated that if a truncated version of cadherin-11 derived from alternative splicing is co-expressed with the full length version of cadherin-11, there is an increase in invasive behavior of the breast cancer cells [33]. Transcriptional regulation of cadherin-11 has not been examined to any great extent in the literature, but at the translational level in breast cancer cells, cadherin-11 expression is down-regulated by β-catenin binding to the 3’ untranslated region directed by glycogen synthase kinase-β [35]. Additionally, interactions between cadherin-11 and fi broblast growth factor receptor 1 occur during the formation of neurite growth cones [36], which may suggest that cadherin-11 in the mammary gland interacts with the FGFRs located there.
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Methylation Abnormalities in Mammary Carcinoma: The Methylation  Suicide Hypothesis

Methylation Abnormalities in Mammary Carcinoma: The Methylation Suicide Hypothesis

Here we use Methyl-MAPS (methylation mapping by paired-end sequencing [4] [5]) to compare the genomic methylation patterns of a series of primary mammary carcinomas with normal breast tissues from the same sub- jects. Methyl-MAPS does not involve preselected primers or probes and yields high coverage, single-CpG reso- lution methylation profiles across the entire genome. The results confirm the reported variable loss of DNA me- thylation from all sequence compartments in carcinomas, but whole genome methylation profiling in primary mammary carcinoma indicates that the frequency of aberrant promoter methylation in this cancer is much lower than previously reported and may not play a major role in carcinogenesis. We suggest that the genome-wide demethylation that commonly occurs in mammary carcinoma may be a manifestation of a methylation-based an- ti-cancer defensive system, and that the silencing of tumor suppressor genes in carcinomas involves pathways other than de novo promoter methylation.
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