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Com a crescente urbanização e individualidade social há o aumento da criação com guarda responsável de animais de estimação, com principais exemplares os cães e gatos, este último como preferencial pelos tutores de forma ascendente nos últimos anos. Naturalmente os felinos podem ter até três gestações no período de um ano, com variação de um a nove filhotes em cada uma delas. Desta forma, a superpopulação destes animais ocorre de maneira exponencial. Esta característica, leva os proprietários a procurar por formas de contracepção para os animais. Dentre as formas existentes, destacam-se a ovariosalpingohisterectomia (OSH) e a contracepção hormonal. Os fármacos anticoncepcionais de maior utilização são os análogos sintéticos da progesterona, como, Acetato de Medroxiprogesterona (AMP), o Acetato de Megestrol e a proligestona. Porém, estes provocam efeitos negativos como hiperplasia endometrial cística, levando à piometra, hiperplasia mamária, resultando em tumores mamários, aborto, diabetes mellitus, dermatopatias e distúrbios comportamentais, portanto não é recomendado o seu uso nesta espécie. Foi realizado um levantamento de dados por meio de questionários, com proprietários de gatas levadas para atendimento clínico do Hospital Veterinário Universitário Jeremias Pereira da Silva da Universidade Federal do Piauí, com o objetivo de analisar quantitativamente os casos de animais com efeitos colaterais, de acordo com a raça e a idade, correlacionado ao uso de fármacos contraceptivos. Os dados obtidos se referem aos meses de março a maio de 2015. Todos os animais descritos neste estudo que apresentaram características patológicas fizeram a utilização de fármacos contraceptivos. Nos 2 casos de piometra encontrados a faixa etária de 4 anos (50%) e 8 anos (50%) foi observada, e todos (100%) os casos ocorreram em gatas Sem Raça definida (SRD). Dos 3 casos de neoplasia mamária, animais com 9 meses correspondem a 33,3%, 1 ano (33,33%) e 2 anos (33,33%) de idade, e todos (100%) eram SRD. Dos 2 casos de abortos, a faixa etária observada foi de 2 anos (50%) e de 3 anos (50%) de idade, e as raças afetadas foram SRD (50%) e siamesa (50%). Dos 2 casos de hiperplasia mamária observados. em gatas com 6 meses (50%) e 8 meses (50%) de idade, e a única raça acometida foi a SRD (100%). Conclui-se que o uso indiscriminado de fármacos contraceptivos ainda é frequente, assim como, é elevada a quantidade de animais que apresentam efeitos negativos ao seu uso.

Pseudoangiomatous stromal hyperplasia (PASH) is a benign hyperplastic condition of the breast that can lead to macromastia. The standard treatment for PASH is focal excision or rarely reduction mammoplasty. We present a rare case of postpartum bilateral rapid breast enlargement and axillary growth that was refractory to reduction mammoplasty. Ultimately, the patient required bilateral mastectomy and two-stage implant-based breast reconstruction. This more extensive form along with its management represents one of the few reported cases in the literature. The decision to pursue bilateral mastectomy was undertaken after exhausting more conservative options. Excellent aesthetic outcome and pain relief was obtained following definitive extirpative and reconstructive surgery.

A hiperplasia mamária felina, também conhecida como hiperplasia fibroepitelial, é caracterizada microscopicamente pelo rápido crescimento do estroma e epitélio ductal das glândulas mamárias em resposta a estímulo hormonal. O objetivo deste trabalho foi relatar um caso que teve um andamento inesperado pela formação de edema após a ovário-salpingo-histerectomia. Uma gata, sem raça definida, com sete meses de idade, nulípara, foi encaminhada ao Departamento de Medicina Veterinária da Universidade Federal de Sergipe, com histórico de aumento de volume de todas as cadeias mamárias há um mês, desenvolvendo os sintomas mencionados dias após a administração de um contraceptivo. Como tratamento, foi proposta a realização da ovário-salpingo-histerectomia com abordagem pelo flanco devido as mamas se apresentarem muito grandes. Após duas semanas houve redução do tecido mamário, porém grande acúmulo de líquido, corroborando para a realização de mastectomia radical no felino. Este relato chama a atenção para considerar a ocorrência deste edema nas mamas após tratamento conservador por meio de ovário-salpingo-histerectomia ou fármacos, já que pode haver uma falsa interpretação de que a mama não esteja reduzindo ou até mesmo aumentando.

In the present study, a rat model of breast hyperplasia was established via the administration of estradiol benzoate and progesterone. Subsequent changes associated with breast hyperplasia were then investigated by measuring the diameter and height of the nipples and by staining breast tissue with hematoxylin and eosin. The proliferation and apoptosis of hyperplastic cells in the breast tissue were then determined by analyzing the expression of proliferating cell nuclear antigen (PCNA) and cleaved-caspase-3 by immunohistochemistry and TUNEL staining. We also determined the expression of proteins associated with the phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) signaling pathway by western blotting. Melatonin treatment led to a significant reduction in the degree of breast hyperplasia (P

Background: Data supporting the use of Chinese herbal medicine compound (CHMC) on breast hyperplasia (BH) based on the data from previous studies. However, the results are still contradictory. Thus, this study aims to compare the results obtained for effect on case-controlled study (CCS) of CHMC on BH. Methods: This study will include CCS assessing the effect of CHMC on BH. A literature search will be carried out in Cochrane Library, MEDLINE, EMBASE, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure from inception to the present. We will not apply language limitation to any electronic database. Study quality will be evaluated using Newcastle-Ottawa Scale, and statistical analysis will be performed using RevMan 5.3 software. Results: This study will summarize the up-to-date evidence to assess the effect of CHMC on BH. Conclusion: The results of this study may exert helpful evidence to determine whether CHMC is effective on BH. OSF registration number: osf.io/3k8ch.

The aim of this article is to present briefly new pathological entities which are recently increasingly commonly used in pathology reports, as well as to discuss their clinical consequences. The new WHO classification of breast diseases includes, inter alia , invasive carcinoma of no special type: this is not a specific entity, but rather a group of malignancies without specific features. The lobular hyperplasia group includes a classical variant and a pleomorphic variant of lobular carcinoma in situ, as well as atypical lobular hyperplasia. The ductal hyperplasia group, according to the current revision of the WHO classification of breast diseases, encompasses: typical (i.e. non-atypical) ductal hyperplasia, columnar cell change, columnar cell hyperplasia, atypical ductal hyperplasia. The mesenchymal breast hyperplasia group includes pseudoangiomatous stromal hyperplasia. We briefly discuss the above mentioned entities together with their respective clinical and therapeutic consequences.

A Hiperplasia mamária felina (HMF) é uma alteração não neoplásica, caracteriza pela proliferação celular do estroma do ducto das glândulas mamárias, comumente diagnosticada no Brasil. Tal alteração muitas vezes é causada pelo uso inadequado de progestágenos exógenos em gatos, que podem ser armazenados no organismo do animal, e sensibilizam as glândulas à proliferação exacerbada por estímulo hormonal. Um dos fatores associados aos casos recorrentes da HMF é a venda desses medicamentos em lojas que prestam serviço de venda de produtos veterinários, aplicados sem restrições e sem conhecimento da fisiologia felina, na tentativa de controle gestacional. A conscientização de tutores sobre os malefícios da aplicação sem critério de progestágenos e a estimulação dos mesmos para que optem por esterilização cirúrgica dos seus animais deve ser feita pelos médicos veterinários, a fim de que se evitem maiores complicações como neoplasia mamária, garantindo, portanto, maior bem estar da população felina. O objetivo dessa revisão é abordar aspectos epidemiológicos, fisiológicos e clínicos, e promover alusão ao uso indiscriminado de anticoncepcionais nessa espécie.

BACKGROUND: The aim of this study was to investigate the effects of artesunate (ART) on breast epithelial cell proliferation in vitro and in vivo. METHODS: Immortalized human non-cancer mammary epithelial (MCF-10A) cells were used to determine the effect of ART on estrogen-induced mammary hyperplasia cells. We investigated the effect of ART on the synthesis of cyclooxygenase-2 (COX-2) and proliferating cell nuclear antigen (PCNA) in MCF-10A by treating MCF-10A 36 h with different concentrations of ART (0, 100, 200, 400 µm, n=12/group). We then investigated the effect of ART on estrogen induced COX-2, PCNA, nuclear factor-kappa B (NF-κB), and pNF-κB synthesis by treating MCF-10A with both estrogen and ART (0, 50, 100, 200 µm, n=12/group). A mammary hyperplasia model (MGH) was established in rats. All rats (n=12) were divided into 4 groups [group A: negative control (NC) + Art −; group B: NC + Art +; group C: MGH + Art −; group D: MGH + Art +] by the random number table method and the effects of ART on estradiol-induced mammary hyperplasia, fibrosis, and phosphorylation of AKT and NF-κB were studied by histopathological staining, Masson trichrome staining, immunohistochemistry (IHC), and western blotting. RESULTS: The proliferation and inflammation of mammary epithelial cells were blocked by ART (P

Introduction: Bilateral breast reduction surgery is the surgical treatment of bilateral breast hypertrophy. This is one of the most common breast surgery requested by women, and performed by plastic surgeons. The reasons that patients want this surgery are to re-size sagging breasts aesthetically, and to get rid of somatic symptoms such as shoulder, chest, back, and neck pain. We believe that the objective positive effects of breast reduction surgery exist beside aesthetic. In our study, our aim is to elicit positive effects of surgery on lungs, if there are, by making pulmonary function test and carbon monoxide diffusion test before surgery and after 6 months of surgery. Materials and Methods: Thirty patients agreed to participate in the study. Study is completed with 19 patients. Pulmonary function test and carbon monoxide diffusion test were made to all patients in preoperative and 6 months of postoperative period. Lung roentgenogram of all patients was performed and height, weight, body mass index were measured. Saturation level was measured. Results: There was a meaningful increase in FEV1 and FVC values in the postoperative period in comparison with pulmonary function test performed in preoperative period. DLCO in postoperative period decreased meaningfully as compared to the preoperative period. Conclusion: Breast reduction surgery seems to have positive effects on pulmonary function test values and relaxes patients clinically. Patients with big breasts should be evaluated from this perspective if they apply chest diseases clinic with shortness of breath. © 2017, Ankara University. All rights reserved.

Breast cancer is estimated to be the leading cancer type among new cases in American women. Core biopsy data have shown a close association between breast hyperplasia and breast cancer. The early diagnosis and treatment of breast hyperplasia are extremely important to prevent breast cancer. The Mongolian medicine RuXian-I is a traditional drug that has achieved a high level of efficacy and a low incidence of side effects in its clinical use. However, for detecting the efficacy of RuXian-I, a rapid and accurate evaluation method based on metabolomic data is still lacking. Therefore, we proposed a framework, named the metabolomics deep belief network (MDBN), to analyze breast hyperplasia metabolomic data. We obtained 168 samples of metabolomic data from an animal model experiment of RuXian-I, which were averaged from control groups, treatment groups, and model groups. In the process of training, unlabelled data were used to pretrain the Deep Belief Networks models, and then labelled data were used to complete fine-tuning based on a limited-memory Broyden Fletcher Goldfarb Shanno (L-BFGS) algorithm. To prevent overfitting, a dropout method was added to the pretraining and fine-tuning procedures. The experimental results showed that the proposed model is superior to other classical classification methods that are based on positive and negative spectra data. Further, the proposed model can be used as an extension of the classification method for metabolomic data. For the high accuracy of classification of the three groups, the model indicates obvious differences and boundaries between the three groups. It can be inferred that the animal model of RuXian-I is well established, which can lay a foundation for subsequent related experiments. This also shows that metabolomic data can be used as a means to verify the effectiveness of RuXian-I in the treatment of breast hyperplasia.

Background In recent years, with the accelerated pace of life, diet, environmental problems occur frequently. External factors are easily to cause endocrine disorders and hormone sensitivity of breast tissue, which can lead to mammary hyperplasia. The incidence rate of hyperplasia of mammary glands is increasing year by year, and the age of onset is also getting lower and lower. If not treated in time, there is a crisis of breast cancer.Clinical studies have found that auricular point pressing therapy is widely used in clinical treatment of mammary hyperplasia recently, but the efficacy of massage in the treatment of mammary hyperplasia has not been systematically reviewed. The purpose of this study is to explore the efficacy, safety and effectiveness of auricular point pressing therapy in the treatment of hyperplasia of mammary glands. Methods We will search PubMed, Web of Science, Cochrane Library, EMBASE, Wan fang Database, Chinese Scientific Journal Database, CNKI, VIP, and Chinese Biomedical Literature Database. The retrieval date was January 10, 2021. RevMan 5.3 software was used to evaluate the quality and risk of included studies. The efficacy, recurrence rate, and symptom score of breast hyperplasia were analyzed, and the results were observed and measured. Results This study will be from the clinical efficiency, improvement rate, pain symptoms disappear rate, tumor size improvement rate, and other aspects of the existing evidence for a high quality synthesis, as well as auricular point pressing therapy adverse events. Conclusion the conclusion of this review will provide the basis for judging whether auricular point pressing therapy is safe and effective in the treatment of hyperplasia of mammary glands. Ethics and dissemination This systematic will evaluate the effectiveness and safety of auricular point pressing therapy in the treatment of hyperplasia of mammary glands. As all data used in this systematic review and meta-analysis have been published, ethical approval is not required for this review. Protocol registration number INPLASY202110028.

Background With the accelerated pace of life, the problems of residence, diet, and environment have occurred frequently in recent years. External factors are easily to cause endocrine disorders and hormone sensitivity of breast tissue, which can lead to mammary hyperplasia. The incidence rate of hyperplasia of mammary glands is increasing year by year, and the age of onset is also getting lower and lower. If not treated in time, there is a crisis of breast cancer.Clinical studies have found that massage is widely used in clinical treatment of mammary hyperplasia recently, but the efficacy of massage in the treatment of mammary hyperplasia has not been systematically reviewed. The purpose of this study is to explore the efficacy, safety and effectiveness of massage in the treatment of hyperplasia of mammary glands. Methods We will search PubMed, Cochrane Central Register of controlled trials (central), ScienceNet, EMBASE, CBM, CNKI, VIP and Wanfang databases. The retrieval date was October 20, 2020. RevMan 5.3 software was used to evaluate the quality and risk of included studies. The efficacy, recurrence rate, and symptom score of breast hyperplasia were analyzed, and the results were observed and measured. Results This study will be from the clinical efficiency, improvement rate, pain symptoms disappear rate, tumor size improvement rate and other aspects of the existing evidence for a high quality synthesis, as well as massage adverse events. Conclusion the conclusion of this review will provide the basis for judging whether massage is safe and effective in the treatment of hyperplasia of mammary glands. Ethics and dissemination This systematic will evaluate the effectiveness and safety of massage in the treatment of hyperplasia of mammary glands. As all data used in this systematic review and meta-analysis have been published, ethical approval is not required for this review. Protocol registration number INPLASY2020100066.

The aim of the present study was to examine Ki-67 expression in tissue of luminal type breast cancer and to investigate the association between the Ki-67 expression level and clinicopathology of breast cancer. A total of 62 patients with breast cancer were included in the study group, whereas 30 patients undergoing a health check-up who were diagnosed with breast hyperplasia were included in the control group. Levels of Ki-67 expression in patients of the two groups were assessed using fluorescent quantitative polymerase chain reaction. The association between Ki-67 and the clinicopathology of the cancer was investigated by analyzing cancer cell proliferation and migration by reducing Ki-67 expression in the human MCF-7 cancer cell line. Compared with the controls, Ki-67 expression was significantly increased in the serum and cancer tissue of breast cancer patients (P

Objective: To evaluate the clinical efficacy of external application of traditional Chinese medicine (TCM) in the treatment of breast hyperplasia. Methods: Randomized controlled clinical trial literatures on external application of TCM in the treatment of breast hyperplasia published in PubMed, Excerpta Medica Database (EMBASE), Cochrane Central Register of Controlled Trials (CENTRAL) , China National Knowledge Infrastructure Database (CNKI) and Chinese Biomedical Abstract Database (CBM) from January 2000 to August 2015 were retrieved, and screened by researchers to data extraction. RevMan 5.3 was applied for Meta analysis. Results: A total of 15 clinical trials with 2 107 patients with breast hyperplasia were included, in which 1 151 were divided into treatment group treated with external application of TCM while 956 into control group. Meta analysis indicated that the clinical response rate and clinical symptom score improvement (lump size) as well as serum levels of estradiol (E2), progesterone (P) and prolactin (PRL) in treatment group were superior to the control group and the differences were statistically significant (PP>0.05). Conclusion: External application of TCM, to some extent, can improve the clinical efficacy in the treatment of breast hyperplasia, and it is necessary to carry out higher-quality, multicenter, large-scale, prospective and double-blind clinical experiments for further validation.

In this work, the clinical significance of changes in the activity of adenosine deaminase (ADA) and the content of polyamines in the blood plasma of cats with breast cancer was studied. There were examined 30 cats aged 1 to 20 years, operated on in veterinary clinics due to spontaneous neoplasms. Histological studies of surgical material were performed to establish nosological forms of the tumor. The results of the measurements showed that there were no significant differences between ADA activity in the blood plasma of cats diagnosed with invasive non-specific carcinoma and ADA activity in the blood of healthy animals. In the plasma of animals diagnosed with fibroadenomatous breast hyperplasia, ADA activity was reduced by 35% compared with the control group. The content of putrescine in the red blood cells of cats with benign neoplasms of the mammary gland (fibroepithelial hyperplasia) was statistically significantly increased 5 times compared with the control group. In malignant neoplasms of the mammary gland (invasive non-specific carcinoma, tubular cancer and fibrosarcoma), the content of putrescine and spermine in the blood significantly exceeded the control values by 60 and 10 times, respectively, compared with the control group. Thus, the data obtained indicate the possibility of using polyamines in order to improve the accuracy of diagnosis and treatment of cats with breast cancer. The determination of ADA activity in the blood plasma of cats with breast tumors in the early stages of cancer is not an informationally significant indicator as a tumor biomarker.

Hyperplasia of mammary glands (HMG) is also termed mammary dysplasia. In China, the number of patients suffering from breast hyperplasia is increasing annually. MicroRNAs (miRNAs; length, 19-24 nucleotides), a group of small endogenous non-coding RNAs, post-transcriptionally regulate gene expression via RNA interference and gene silencing pathways. The cause of disease of HMG because remains unclear. Thus, the aim of the present study was to establish comprehensive profile of drug treatments following at different time intervals on rat models of differentially expressed miRNAs, using miRNA microarray data. After scanning the chip, 13 up-regulated and 20 down-regulated miRNAs were identified. MiR-31 and miR-30 exhibited different expression levels between rats exhibiting mammary gland hyperplasia treated with or without Jiedu Capsule water solution once a day for 4 weeks, and the two demonstrated a strong association with HMG and breast cancer. Therefore, the functions of these miRNAs may provide the basis for further investigation of HMG.

Introduction: Abnormal proliferation in the breast is clinically seen ranging from hyperplasia to atypia to in situ carcinomas (DCIS) to invasive cancers. Whether these states comprise points along an evolutionary continuum is a subject of debate, but has significant implications for prevention, prognosis, and treatment. Due to the length of time involved, tumor evolution is difficult to study in vivo and in vitro models. We hypothesize a continuum from hyperplasia to cancer can be demonstrated by examining patterns of accumulated mutations in tumors. We employ a previously developed computational model of ductal epithelial dynamics, the DEABM (1), to simulate and track accumulated mutations during the progression from a normal epithelial population through hyperplastic states to the development of invasive tumors Methods: Simulation experiments were performed using an expanded DEABM, which incorporates the functions of luminal and myoepithelial cells, their progenitors and fibroblasts. DNA damage can potentially disrupt 12 functional pathways regulated by oncogenes and tumor suppressors implicated in breast cancer (BRCA1, P53, E-cadherin, RUNX3, Myc, ER, TGF-b, MMP-3, EGFR, HER-2 and Telomerase). The expanded DEABM allows for sequential tracking of genetic lesions in each cell. 3,000 simulations in both wild-type (WT) and BRCA1-mutated states were run over 40 years of simulated menses. Cell populations were characterized as normal, hyperplastic or malignant based on quantitative cell expansion from baseline, as well as by mutational profiles, sequential order of mutations and ER status. Results: Tumor profiles approximated epidemiologic rates of cancer incidence and ER/HER2 status. 2.6 % of WT developed malignancy vs. 45.9% of BRCA1. WT tumors were 54% ER+/HER2-, 17% ER+/HER2+, 6% ER-/HER2+ and 22% ER-/HER2-. BRCA1 tumors were 29% ER+/HER2-, 7% ER+/HER2+, 13% ER-/HER2+ and 50% ER-/HER2-. Hyperplastic populations carried more mutations than non-hyperplastic populations (p>.01) and were more likely to carry mutations in telomerase, E-cadherin and genes related to ER expression (TGFB, RUNX3, p Conclusion: The DEABM generates diverse tumors that express tumor markers consistent with epidemiologic data. The DEABM also generates non-invasive, hyperplastic populations, analogous to atypia and/or DCIS, via mutations to genes known to be present in hyperplastic lesions and early mutations in breast cancers. The results demonstrate that agent-based models are well-suited to studying tumor evolution through stages of carcinogenesis and have the potential to be used to develop prevention and treatment strategies. Ref: Chapa J, et al. "Examining the Pathogenesis of Breast Cancer Using a Novel Agent-Based Model of Mammary Ductal Epithelium Dynamics." PloS one 8.5 (2013). Citation Format: Joaquin Chapa, Gary An, Swati A Kulkarni. Demonstration of the evolutionary dynamics of the progression from breast hyperplasia to cancer using the duct epithelial agent based model (DEABM) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-08-03.

To explore the efficacy of psychological interventions (PI) in patients with breast hyperplasia (BH). In total 120 BH patients who were treated in the Third Affiliated Hospital of the Third Military Medical University were randomly divided into PI group (n = 40; treated with oral XiaoYao Pill and psychological interventions), anti-anxiety/depression medication (AADM) group (n = 40; treated with oral XiaoYao Pill and paroxetine), and control group (n = 40; treated with oral XiaoYao Pill) and the treatment lasted for 1 year. Before the treatment and 4, 8, and 12 months after the initiation of treatment, the changes in the psychological indicators were measured using Toronto Alexithymia Scale (TAS), Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), and Ways of Coping Questionnaire (WCQ), as well as the physiological indicators including estradiol, prolactin, and progesterone were determined. The overall response rates were evaluated at the end of the treatment, and the relapse rates were calculated during the 1-year follow-up. The HAMD and HAMA scores were declined in all three groups. The scores of TAS and WCQ negative coping subscales showed a declining trend after treatment for the AADM and PI groups. Compared to the control and PI groups, the HAMA and HAMD scores were significantly lower in the AADM group 4, 8, and 12 months after the initiation of treatment (P P P P P P > 0.05), while the relapse rate was significantly lower in the PI group than the control and AADM groups (P P > 0.05). PI can effectively improve the psychological status of BH patients and restore the disordered endocrine system. The efficacy lasts for long and the relapse rate is lower. Therefore, it could be an effective method for treating BH.

The objective of the present study was to investigate a comparative estimation screening method of prostate specific antigen levels in serum samples with immunohistochemistry results for analysis expression of prostate specific antigen in female breast tissues at benign breast hyperplasia and breast cancer. This study was applied on 65 women suffering from breast cancer, 31 of them have benign breast hyperplasia and 34 have malignant breast cancer. Each group was divided into 2 subgroups, pre and postmenopause, both subgroups were compared with 15 normal cases to assess serum and tissue PSA in benign and malignant patients in pre and post menopause state by immunoradiometric assay in blood and immunohistochemistry in tissue. No significant difference in serum Total PSA concentration between any of the studied cases. However, there were different variations in the distribution of PSA in the breast tumor tissue, with complete absence of PSA in the tissue samples of the malignant in postmenopausal patients. In conclusion, PSA presence in benign breast hyperplasia in either serum or tissue may show clinical value regarding the diagnosis and prognosis of the disease.

Aromatase is essential for estrogen production and is the target of aromatase inhibitors, the most effective endocrine treatment for postmenopausal breast cancer. Peripheral tissues in women, including the breast, express aromatase via alternative promoters. Female mice lack the promoters that drive aromatase expression in peripheral tissues; thus, we generated a transgenic humanized aromatase (Aromhum) mouse line containing a single copy of the human aromatase gene to study the link between aromatase expression in mammary adipose tissue and breast pathology. Aromhum mice expressed human aromatase, driven by the proximal human promoters II and I.3 and the distal promoter I.4, in breast adipose fibroblasts and myoepithelial cells. Estrogen levels in the breast tissue of Aromhum mice were higher than in wild-type mice, whereas circulating levels were similar. Aromhum mice exhibited accelerated mammary duct elongation at puberty and an increased incidence of lobuloalveolar breast hyperplasia associated with increased signal transducer and activator of transcription-5 phosphorylation at 24 and 64 wk. Hyperplastic epithelial cells showed remarkably increased proliferative activity. Thus, we demonstrated that the human aromatase gene can be expressed via its native promoters in a wide variety of mouse tissues and in a distribution pattern nearly identical to that of humans. Locally increased tissue levels, but not circulating levels, of estrogen appeared to exert hyperplastic effects on the mammary gland. This novel mouse model will be valuable for developing tissue-specific aromatase inhibition strategies.

Uncontrolled proliferation is one of the hallmarks of breast cancer. We have previously identified the human Ecd protein (human ortholog of Drosophila Ecdysoneless, hereafter called Ecd) as a novel promoter of mammalian cell cycle progression, a function related to its ability to remove the repressive effects of Rb-family tumor suppressors on E2F transcription factors. Given the frequent dysregulation of cell cycle regulatory components in human cancer, we used immunohistochemistry of paraffin-embedded tissues to examine Ecd expression in normal breast tissue versus tissues representing increasing breast cancer progression. Initial studies of a smaller cohort without outcomes information showed that Ecd expression was barely detectable in normal breast tissue and in hyperplasia of breast, but high levels of Ecd were detected in benign breast hyperplasia, ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDCs) of the breast. In this cohort of 104 IDC patients, Ecd expression levels showed a positive correlation with higher grade (P = 0.04). Further analyses of Ecd expression using a larger, independent cohort (954) confirmed these results, with a strong positive correlation of elevated Ecd expression with higher histological grade (P = 0.013), mitotic index (P = 0.032), and Nottingham Prognostic Index score (P = 0.014). Ecd expression was positively associated with HER2/neu (P = 0.002) overexpression, a known marker of poor prognosis in breast cancer. Significantly, increased Ecd expression showed a strong positive association with shorter breast cancer specific survival (BCSS) (P = 0.008) and disease-free survival (DFS) (P = 0.003) in HER2/neu overexpressing patients. Taken together, our results reveal Ecd as a novel marker for breast cancer progression and show that levels of Ecd expression predict poorer survival in Her2/neu overexpressing breast cancer patients. Electronic supplementary material The online version of this article (doi:10.1007/s10549-011-1946-8) contains supplementary material, which is available to authorized users.

RuXian-I has traditionally been used as a remedy for breast hyperplasia in the Inner Mongolia Autonomous Region of China. As a first step toward the investigation of biomarkers associated with RuXian-I treatment, a proteome-wide analysis of rat breast tissue was conducted. First, rat breast hyperplasia was induced by injection of estradiol and progesterone. After treatment with RuXian-I, there is a marked decrease in the hyperplasia, as can be shown by decreases in the nipple diameter and the pathological changes in breast. Subsequently, we used an approach that integrates size-based 2D-DIGE, MALDI-TOF/TOF-MS, and bioinformatics to analyze data from the control group, the model group and the RuXian-I treatment group. Using this approach, seventeen affected proteins were identified. Among these, 15 (including annexin A1, annexin A2, superoxide dismutase [Mn], peroxiredoxin-1, translationally-controlled tumor protein and a B-crystallin) were significantly up-regulated in the model group and down-regulated upon treatment with RuXian-I, and two (Tpil protein and myosin-4) have the opposite change trend. The expression of annexin A1 was confirmed using immunohistochemistry. The expression of superoxide dismutase (SOD) activity was confirmed biochemically. These results indicated that RuXian-I treats rat breast hyperplasia through regulation of cell cycle, immune system, metabolic, signal transduction, etc. The differential expressions of these proteins (annexin A1, superoxide dismutase [Mn], alpha B-crystallins and translationally controlled tumor protein, among others) were associated with occurrence and metastasis of breast cancer. These findings might provide not only far-reaching valuable insights into the mechanism of RuXian-I action, but also leads for prognosis and diagnosis of breast hyperplasia and breast cancer.

BACKGROUND: The precise timing of the angiogenic switch and the role of angiogenesis in the development of breast malignancy is currently unknown. METHODS: Therefore, the expression of CD31 (pan endothelial cells (ECs)), endoglin (actively proliferating ECs), hypoxia-inducible factor-1 (HIF-1alpha), vascular endothelial growth factor-A (VEGF) and tissue factor (TF) were quantified in 140 surgical specimens comprising normal human breast, benign and pre-malignant hyperplastic tissue, in situ and invasive breast cancer specimens. RESULTS: Significant increases in angiogenesis (microvessel density) were observed between normal and benign hyperplastic breast tissue (P

Purpose The NOEY2 gene mutations and protein expression in human breast cancers, adjacent breast tissues and breast benign lesions were analysed to explore the potential correlation between the mutation spectrum and breast cancer development and progression. Experimental design The promoter, exon and intron regions of NOEY2 gene were amplified by polymerase chain reaction (PCR) with DNA extracted from 50 human breast cancer and corresponding adjacent breast tissues as well as 50 breast benign lesions, respectively. The PCR products were then sequenced and analysed. The effect of mutations on the expression of NOEY2 protein by immunohistochemistry were proven as well. Results Twenty-one of 50 (42%) breast cancer mutations were identified in promoter (11 cases) and exon 2 (seven cases on untranslation region and three on coding region) and 17 of 50 (34%) adjacent breast tissues (all were atypical hyperplasia lesions) occurred mutations, including six promoter mutations and 11 exon 2 changes (10 cases on untranslation region and one on coding region). Interestingly, the mutations were identified in both breast cancers and the corresponding adjacent breast tissues collected from the same patient in seven of them. No mutation was identified in all benign breast tissues. Immunohistochemical analysis showed that two of 17 mutational adjacent breast tissue samples were NOEY2 immunoreaction negative, and in all 21 mutations of breast cancers five cases were of loss of NOEY2 expression. All mutations with immunoreaction negative factor were located at promoter and/or exon 2 coding region. NOEY2 gene mutations were not correlated with patient ages, histological types, tumour sizes, histological grades, clinical stages, axillary lymph node metastases or with the condition of hormone receptor (ER, PR) expression and HER2 amplification. Conclusions The mutations of human NOEY2 were identified in human breast cancers and the corresponding adjacent breast tissues. The hot mutation spots were its promoter and exon 2 regions, and those occurring at the exon2 coding region and part of the promoter may alter the expression of NOEY2. The presence of NOEY2 mutations in human breast cancer and early-stage lesions indicates that NOEY2 mutations may be partly associated with breast tumourigenesis.

The cyclooxygenase-2 (COX-2) enzyme, which is induced by inflammatory and mitogenic stimuli, plays a protumorigenic role in several human cancers. COX-2 is overexpressed in invasive and in situ breast cancers. Atypical hyperplasia in breast tissue, although benign, is associated with a high risk of breast cancer. We investigated whether COX-2 overexpression in atypical hyperplasia is associated with the risk of subsequent breast cancer.COX-2 expression was assessed immunohistochemically in archival sections from 235 women with atypia whose biopsy specimens were obtained at the Mayo Clinic from January 1, 1967, through December 31, 1991. COX-2 expression was scored as 0 (negative), 1+ (weak), 2+ (moderate), or 3+ (strong). Risk factor information and follow-up for breast cancer events were obtained via a study questionnaire and the medical records. All statistical tests were two-sided.Forty-one (17%) of the 235 women developed breast cancer during a median follow-up of 15 years. Moderate (category 2+) or strong (category 3+) COX-2 expression was identified in 71 (30%) and 34 (14%) of the 235 samples, respectively. The risk for developing breast cancer, relative to a control population (the Iowa Surveillance, Epidemiology, and End Results registry), increased with increasing COX-2 expression (relative risk [RR] = 2.63, 95% confidence interval [CI] = 1.56 to 4.15, for those with negative or weak COX-2 expression; RR = 3.56, 95% CI = 1.94 to 5.97, for those with moderate expression; and RR = 5.66, 95% CI = 2.59 to 10.75, for those with strong expression; P = .07). Overexpression of COX-2 was statistically significantly associated with the type of atypia (lobular vs ductal, P.001), number of foci of atypia in the biopsy (P = .02), and older age at time of biopsy (45 years, P = .01).COX-2 appears to be a biomarker that further stratifies breast cancer risk among women with atypia and may be a relevant target for chemoprevention strategies.

To detect the expressions of E-cadherin, α-catenin and β-catenin and analyze the relationship between E-cadherin-catenin adhesion complex and clinicopathological features in breast cancer. The expressions of E-cadherin, α-cadherin and β-catenin in specimens of 54 breast cancer, 21 normal breast tissues around tumor, 15 breast hyperplasia of usual type and 15 breast atypical hyperplasia were detected by immunohistochemical method. In 21 normal breast tissues, E-cadherin and α-catenin were expressed on cell membrane of ductal and acinic cells, showing cellular contour and border among cells. The staining character of the three proteins in breast hyperplasia of usual type was the same as that in normal breast tissue. In breast atypical hyperplasia, the abnormal expression rates of E-cadherin, α-catenin and β-catenin were 6.7%, 13.3% and 26.7%, respectively. The total abnormal expression rate of E-cadherin-catenin complex was 33.3%. In breast cancer, the abnormal expression rates of E-cadherin, α-catenin and β-catenin were 51.9%, 63.0% and 61.1%, respectively. The total abnormal expression rate of E-cadherin-catenin complex was 88.9%. Abnormal expression of E-cadherin and α-catenin were significantly correlated with histological grade. Abnormal expressions of α-catenin and β-catenin were significantly correlated with TNM staging, axillary lymph nodes metastasis and postoperative distant metastasis. Abnormal expression of E-cadherin-catenin complex was correlated with TNM staging, histological grade and axillary lymph nodes. Abnormal expression of β-catenin was negatively correlated with expression of HER-2. COX multiple factor analysis showed that E-cadherin or α-catenin or β-catenin was not independent prognostic indicator. Abnormal expressions of E-cadherin, α-catenin and β-catenin frequently occur in breast cancer. Abnormal expression of E-cadherin-catenin complex is correlated with differentiation disturbance and metastasis. Combined measurement of E-caherin, α-catenin and β-catenin may improve accuracy and sensitivity of predicting metastasis and prognosis of breast cancer.

Dietary phytosterol supplements are readily available to consumers since they effectively reduce plasma low-density lipoprotein cholesterol. Several studies on cell cultures and xenograft mouse models suggest that dietary phytosterols may also exert protective effects against common cancers. We examined the effects of a dietary phytosterol supplement on tumor onset and progression using the well-characterized mouse mammary tumor virus polyoma virus middle T antigen transgenic mouse model of inherited breast cancer. Both the development of mammary hyperplastic lesions (at age 4 weeks) and total tumor burden (at age 13 weeks) were reduced after dietary phytosterol supplementation in female mice fed a high-fat, high-cholesterol diet. A blind, detailed histopathologic examination of the mammary glands (at age 8 weeks) also revealed the presence of less-advanced lesions in phytosterol-fed mice. This protective effect was not observed when the mice were fed a low-fat, low-cholesterol diet. Phytosterol supplementation was effective in preventing lipoprotein oxidation in mice fed the high-fat diet, a property that may explain - at least in part - their anticancer effects since lipoprotein oxidation/inflammation has been shown to be critical for tumor growth. In summary, our study provides preclinical proof of the concept that dietary phytosterols could prevent the tumor growth associated with fat-rich diet consumption. © 2013 Elsevier Inc.

Cowden's disease is a rare entity accompanied with caracteristic mucocutaneous lesions, gastrointes-tinal polyposis, thyroid hyperplasia and breast hyperplasia. We describe a case of Cowden's disease in a 55-year-old woman accompanied with bilateral breast cancers, colon cancer and gastrointestinal polyposis. There were previous histories of undergoing operations for a goiter, left breast cancer, and right breast cancer when she was 40, 50, and 52 years old, respectively. Physical findings showed small popule on the face and extremities and papillomatous oral lesion. X-ray and endoscopic examinations revealed multiple polyps in the esophagus, stomach, duodenum and colon and a cancer of the sigmoid colon. Sigmoidectomy was performed. Histological findings of the cancer was well differenticated adenocarcinoma invaded the propria muscle and those of polyps indicated hyperplastic polyp. It has been reported that Cowden's disease is accompanied with malignant tumor in a high frequency and based on a review of the Japanese literature, malignant lesion have been reported in 18 out of 49 cases. When adiagnosis of Cowden's disease is made, we should screen probable maliganant lesions.

Benign breast hyperplasia is a diseases of civilization associated in women with hormonal disorders, estrogen dominance syndrome. Risk of developing breast cancer for women with proliferative forms of benign breast disease increased tenfold. Absolutely all patients seek medical attention, regardless of pathology, must undergo breast examination and obtain recommendations for the prevention and the multiplicity of diagnostic tests. An important role in the pathogenesis of benign breast hyperplasia plays an increase prolactin levels. Hyperprolactinemia is a frequent cause of menstrual and generative dysfunctions, as well as benign breast hyperplasia, which negatively affects the quality of women life. Quite often there is not a permanent but temporary (latent or hidden) increase prolactin secretion. Occasional bursts of prolactin levels, combined with hyperestrogenemia cause bloating, breast tenderness (mastalgia). Hyperprolactinemia induced menstrual dysfunction causes abnormal steroidogenesis in the ovaries, which also exacerbates the morphological and functional abnormalities in the mammary glands, promotes dishormonal breast diseases and increases the risk of breast cancer. Due to the increase of cancer incidence in all countries is increased emphasis on early tumors diagnosis and prevention. Special nutrition and various diets are considered as one of the variants of the anti-tumor protection. Numerous studies in recent years devoted phytonutrients – substances of plant origin. Phytopreparation that can be used in these disorders is Epigalin Brest® that contained indole-3-carbinol, epigallocatechin-3-gallate and Vitex agnus castus extract. Indole-3-carbinol and epigallocatechin-3-gallate are biologically active substances with a well-deserved popularity among clinicians in Europe and the United States. Herbal drug Epigalin Brest® regulates the metabolism of estrogen by blocking the synthesis of its “aggressive” forms, reduces the level of prolactin, inhibits the abnormal proliferation in hormone-dependent organs (mammary gland) and tissues of the reproductive system. Also Epigalin Brest® has antiproliferative effects.

CREB-2, also known as ATF-4, belongs to the CREB proteins, a family of transcription factors phosphorylated at serine residues by protein kinase A (PKA). This family is known to stimulate the transcription of genes containing CRE elements. Recently, some studies have demonstrated elevated CREB-2 expression in certain tumor types, including breast carcinoma, compared to their corresponding non-tumor tissues. However, the expression and clinical significance in malignant tumors, including breast carcinoma, of p-CREB-2 (ser 245), a phosphorylated form of the CREB-2 protein at serine 245 site, which is believed to be an active type of this protein, have not been clearly documented. In the present study, we investigated the expression of p-CREB-2 (ser 245) in a group of tumor and non-tumor breast tissues, including normal breast epithelia, hyperplasia, dysplasia, carcinoma in situ and infiltrating carcinoma of the breast using tissue microarray and immunohistochemistry (IHC). p-CREB-2 (ser 245) immunostaining was detected in the nucleus and cytoplasm of these tissues. Compared to normal breast epithelia and breast hyperplasia (total positive rate 13.3%), there was increased expression of p-CREB-2 (ser 245) in dysplasia, carcinoma in situ (total positive rate 35.7%) and infiltrating carcinoma of the breast (total positive rate 60.0%) (p

Obesity has been associated with abnormally high expression of the enzyme aromatase in the breast, increased local estrogen production, and predisposition to breast hyperplasia and cancer. Increased adiposity in postmenopausal women may trigger signaling pathways that induce aromatase expression. In breast adipose fibroblasts, increased TNF production may induce the distal aromatase promoter, whereas increased local PGE(2) production may induce the proximal promoter region. We review here the mechanisms that control aromatase gene expression in breast adipose tissue, and the paracrine interactions between malignant breast epithelial cells and the surrounding adipose fibroblasts. Systematic characterization of these signaling pathways will facilitate the identification of potential drug targets to selectively reduce aromatase expression and excessive estrogen production, with therapeutic benefit.

BACKGROUND. Atypical lobular hyperplasia (ALH) is associated with a 10% to 20% risk of subsequent invasive carcinoma, primarily in the ipsilateral breast. Nottingham grading, special tumor types, and survival after invasive cancer diagnosis were analyzed consistently for the first time. METHODS. A longitudinal follow-up study of 252 women who underwent 261 benign surgical biopsies between 1950 and 1985 with a diagnosis of ALH was undertaken. Subsequent invasive breast cancers were graded and subtyped based on histologic features and the cohort assessed for cancer survival. RESULTS. Forty-eight (19%) women developed invasive breast cancer at an average of 15.1 years. Twenty (42%) of the tumors were special subtype tumors with good prognosis. By an average of 13 years after invasive cancer diagnosis, 2 (10%) of 20 women with special type and variant tumors had died of breast cancer, compared with 9 (32%) of 28 women with tumors of no special type (24 tumors) or an unknown type (4 tumors). Only 1 patient with a tumor of low Nottingham grade died of breast cancer. CONCLUSIONS. ALH is a nonobligate cancer precursor associated with a moderate risk of breast cancer and predicts that later cancers are associated with overall excellent survival. Nearly half of the subsequent cancers show classic or variant patterns of special types with a good prognosis and the majority are of low or intermediate combined histologic grade. Treatment of women with ALH should be influenced by their modest elevation in breast cancer risk and the good prognosis and low mortality of many of these cancers. Cancer 2006. © 2006 American Cancer Society.

A diagnosis of atypical ductal hyperplasia (ADH) after breast core biopsy usually is followed by an excisional biopsy to exclude the presence of a more significant lesion. To determine whether the immunohistochemical expression of cyclin D1 (CyD1) and Ki-67 can aid in case stratification for the likelihood of finding ductal carcinoma in situ (DCIS) on subsequent excision, we immunohistochemically stained 21 consecutive ADH cases diagnosed by core biopsy, and proliferation indices (PIs) were calculated for each case. Fluorescence in situ hybridization to detect CCND1 amplification was performed in 10 cases. In 5 cases, DCIS (with or without invasive carcinoma) was identified in the subsequent excision. The mean PI CyD1 and PI Ki-67 for these cases were significantly higher than in the remainder (P = .03 and P = .05, respectively). The sensitivities of PI CyD1 and PI Ki-67 for the presence of DCIS on subsequent excision were 100%, and the specificities were 75% and 69%, respectively. The specificity of the 2 markers combined was 88%. The number of cells with CCND1 amplification was higher in cases with DCIS or ADH on subsequent excision. Immunostaining for CyD1 and Ki-67 might help stratify cases of ADH on core biopsy and identify patients unlikely to have DCIS found on excision.

To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. Continued overexpression of aromatase that leads to increased breast-tissue estrogen contributes to a number of epigenetic changes in mammary tissue such as alteration in the regulation of genes involved in apoptosis, activation of genes involved in cell cycle and cell proliferation, and activation of a number of growth factors. Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast hyperplasia and these changes can be abrogated using aromatase inhibitors.

Purpose: The need for surgical excision in patients with ultrasound-guided core needle biopsy (CNB)-diagnosed atypical ductal hyperplasia (ADH) remains an issue of debate. The present study sought to validate a scoring system (the U score, for underestimation) that we have previously developed for predicting malignancy in CNB-diagnosed ADH. Methods: The study prospectively enrolled 85 female patients with CNB-diagnosed ADH who underwent subsequent surgical excision. Underestimation was defined as a surgical specimen having malignant foci. Results: The overall underestimation rate was 37% (31/85). Multivariate analysis showed that a clinically palpable mass, microcalcification on imaging, size > 15 mm and a patient age of ≥ 50 years were independently associated with underestimation. When applied to the scoring system, the validation score was significant (p< 0.001; area under the curve, 0.852). No patient with a U score < 3.5 had an underestimated lesion. Conclusion: The present study successfully validated the efficacy of our scoring system for predicting malignancy in CNB-diagnosed ADH. A U score of ≤ 3.5 indicates that surgical excision may not be necessary.

The purpose of this study was to investigate if ibuprofen intake can influence mammary uptake of the proliferation-seeking radiotracer technetium 99m-pentavalent dimercaptosuccinic acid (99mTc-(V)DMSA) in women with severe epithelial and atypical epithelial breast hyperplasia. Eight patients with histologically confirmed severe epithelial breast hyperplasia with (n = 4) and without atypia (n = 4) were submitted prospectively to 99mTc-(V)DMSA scintimammography before and after a 4-week course of 400 mg ibuprofen daily oral intake. Lesion to background ratios 60 minutes postinjection were calculated and compared (t-test) before and after ibuprofen administration. Prior to ibuprofen, the patients with severe epithelial hyperplasia displayed a significantly higher 99mTc-(V)DMSA uptake ratio compared to those with atypical epithelial hyperplasia (2.40 ± 0.32 vs 1.67 ± 0.09, respectively; p = .003). They also exhibited a more substantial percent decline in tracer uptake postibuprofen compared to women with atypical epithelial hyperplasia (62.0 ± 7.1 vs 15.0 ± 0.2, respectively; p = .001). Ibuprofen induces significant uptake reduction of the proliferation-seeking radiotracer 99mTc-(V)DMSA in severe epithelial breast hyperplasia without atypia. This agent could therefore constitute a potential imaging tool for monitoring chemoprophylaxis effectiveness in women at the early stages of malignant transformation.

Breast core needle biopsy (CNB) is an established method for diagnosing benign and malignant breast disease and CNB is widely used in daily practice. However, CNB samples only part of a lesion, and this can be the reason for an inaccurate diagnosis.(1) This size limitation of CNB gives rise to important diagnostic problems because one of the important factors for making the differential diagnosis between atypical ductal hyperplasia (ADH) and lowgrade ductal carcinoma in situ (DCIS) is the size of the lesion.(2,3) Previous studies have reported that ADH in a CNB showed significant discordance in the subsequent surgical excision specimens for which 33-87% demonstrated ductal carcinoma such as DCIS and invasive ductal carcinoma (IDC).(4-11) Therefore, surgical excision is presently recommended when ADH is diagnosed in a CNB. Investigations to determine the factors that are predictive of more advanced lesions in surgical excision specimens when ADH was diagnosed in the CNB have suggested cytologic atypia,(11) more than 4 foci (7) and micropapillary architecture (7), yet consistent results were not demonstrated. The purpose of this study was to identify the predictive factors that suggest the diagnosis of ductal carcinoma in the subsequent surgical excision specimens when ADH is diagnosed in a CNB.

Hyperplasia of the breasts is regularly noted in pregnancy. This change in the breasts, for a time passively accepted as a fact, has in late years been made the subject of intensive study, which aimed to discover the primary cause of the tissue growth, and to analyze the nature of the stimulus which gave rise to it. The subject is not only of great interest to biologists, but to investigators in all branches of medicine. The sweeping analogies, drawn from some of the theories which have been based on experimental work, are so far-reaching that confirmation is imperatively needed; otherwise there is danger of basing future research, some in allied, others in entirely separate fields, on an insecure or even false foundation. The breast hyperplasia of pregnancy can best be studied in animals, and as a matter of laboratory convenience, small animals are preferred. Most workers have employed