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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.

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

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.

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.

Pseudo Angiomatous Stromal Hyperplasia (PASH), a benign disease with extremely low incidence, is manifested as giant breasts, frequent relapse after surgery, or endocrine disorder. Cases with unilateral breast and undetailed endocrine condition have been reported in African and American. In this case, a 19-year-old Asian girl suffered from bilateral breast PASH after the human placenta and progesterone treatment for 3-month delayed menstruation. Her breasts enlarged remarkably 1 month after the treatment, with extensive inflammatory swell in bilateral mammary glands and subcutaneous edema in retro mammary space. The patient received the bilateral quadrantectomy plus breast reduction and suspension surgery to terminate the progressive hyperplasia of breast. During the whole treatment period, the patient was given tamoxifen treatment for 4 months, and endocrine levels were intensively recorded. The follow-up after 4 months showed recovered breast with normal shape and size, and there was no distending pain, a tendency toward breast hyperplasia, or menstrual disorder. Level of Evidence: Level IV, case study. Keywords: Pseudo angiomatous stromal hyperplasia; 19-year-old Asian girl; Tamoxifen

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.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is one of the most frequently mutated human tumor suppressor genes. The present study aims to investigate the role of PTEN mutation in breast carcinogenesis by analyzing PTEN mutation spectrum and the protein expression in breast cancers, adjacent hyperplastic lesions, benign breast lesions and normal breast tissues. All 9 exons of PTEN gene were amplified by PCR with DNA extracted from 50 of human breast cancers and corresponding adjacent breast hyperplasia tissues, adjacent normal breast tissues, as well as 50 breast benign lesions residing in or around Yunnan, China, respectively. PCR products were then sequenced for mutation screening. And we also proved the effect of mutations on the expression of PTEN protein by immunohistochemistry. PTEN mutations were detected in 11 of 50 (22%) breast cancers and 4 of 50 (8%) adjacent ductal hyperplasia, all of which were atypical ductal hyperplasia and same PTEN mutation were detected in the corresponding cancer tissues. No PTEN mutation was detected in all adjacent normal breast tissues and 50 cases of breast benign lesions. The mutation sites concentrated at exon 3, 4, 5 and 7; no mutation was detected in exon 1, 2, 6, 8, or 9 and splicing sites of all introns. The hottest mutation spots were exon 5 with missense mutations. Immunohistochemical analysis showed that 24 of 50 (48%) breast cancers and 6 of 50 (12%) adjacent breast hyperplasia demonstrated negative immuno-staining of PTEN (loss of PTEN protein expression). All the 4 adjacent breast tissues harbored PTEN mutations and 9 of 11 breast cancers with PTEN mutation were loss of PTEN expression. Statistical analysis revealed that PTEN gene mutations were correlated with the PTEN expression. The incidence of PTEN mutations is relatively high in patients with sporadic breast cancer in the region of Yunnan, China and exists at the early stage of breast cancer development. The PTEN mutations have significant effect on the expression silencing of PTEN protein indicating the important role of PTEN mutation in carcinogenesis of breast cancers.

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.

It remains unclear whether hyperplastic breast lesions, especially with atypia, are cancer precursors or markers of increased cancer risk. Quantified comparisons of genomic alterations in coexisting lesions could address this question. Therefore, we examined allele imbalance (AI), also known as loss of heterozygosity (LOH), at 20 microsatellite markers on nine chromosome arms, in DNA from 106 samples microdissected from 17 randomly selected cancer-containing breast specimens: 13 simple (DH) and 45 atypical ductal hyperplastic (ADH) lesions, 30 in situ (DCIS) and 18 invasive ductal carcinomas (IDC). Data were analysed using regression models and generalized estimating equations. We found that AI increased as histology became more aberrant and varied with histology across the chromosome arms (p

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

Expressions of Notch1 and Cyclin D1 were analysed by immunohistochemical method in the specimens of normal mammary tissue, usual hyperplasia, atypical hyperplasia, cancer in situ, and invasive cancer tissue, which were obtained from the patients operated due to some kind of breast disease. We observed an evidently decreased Notch1 and increased cyclin D1 expression respectively from normal tissue to invasive cancer, and a negative correlation was drawn between Notch1 and Cyclin D1. No correlation was found between Notch1 expression and any clinicopathologic parameter, but there was positive correlation between the Cyclin D1 expression and ER. This indicated the inhibiting function of Notch1 and promoting function of Cyclin D1 in proliferating process of mammary ductal tissue. From hyperplasia to cancer, there is a continus and sequential process, which suggest an intimate relationship between mammary hyperplasia and breast cancer. Key words-mammary ductal hyperplasia; invasive mammary cancer; Notch1; Cyclin D1; immunohistochemistry

Previous studies have shown the chromosomal alterations in usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) in the breast with bilateral ductal hyperplasia or adjacent to invasive ductal carcinoma (IDC). However, the role of UDH as a putative precursor of breast IDC is not clear and has not been fully addressed. The aim of this study was to clarify the role of UDH in breast carcinoma pathogenesis. To investigate chromosomal imbalances and commonality, samples of pure unilateral UDH (n=20) were obtained by laser capture microdissection and analyzed by comparative genomic hybridization. Other ductal lesions, including ADH (n=2), high-grade DCIS (n=3), and grade III IDC (n=5), were assessed at the same time for comparison. The mean values of alteration were 1.95 (39/20) in UDH, 9.5 (19/2) in ADH, 11.0 (33/3) in DCIS and 18.2 (89/5) in IDC, respectively. Some common predisposition regions for the deletions were at chromosomes 1p36-pter, 13q11-14, and 16q11-23, while the high frequency amplification regions were 1q31-qter, 3p21-pter, 6p21-pter, 11q11-14, 12q11-qter, 13q21-qter, 16p12-pter, 17q12-22, and 20q. The genetic abnormalities in the spectrum of breast ductal hyperplasia revealed that the deletion of DNA copy in UDH was the lowest, and gradually increased in the lineages of ADH, DCIS and IDC. Results showed that a significant portion of UDH shares common genetic alterations with ADH, DCIS and IDC, indicating UDH as a precursor of invasive breast ductal carcinoma.

To estimate whether breast uptake of (99m)Tc-(V)DMSA and (99m)Tc-sestamibi in usual ductal epithelial breast hyperplasia (UDH) and apocrine metaplasia is related to cell proliferation rate (Ki-67) and oestrogen receptor (ER) expression, both of which are associated with the potential risk of evolving to malignancy.Among patients referred for suspicious breast findings on palpation and/or mammography and evaluated preoperatively with both radiopharmaceuticals, we retrospectively studied 17 (10 with UDH: group I; and seven with apocrine metaplasia: group II). Lesion-to-background (L/B) ratios in early and late acquisitions were calculated for both radiotracers in both groups, as well as their retention ratios. Ki-67 and oestrogen receptor expression were determined immunohistochemically. The late L/B ratios between the two tracers were compared, as were the late ratios for each tracer between Ki-67or = 3% and3%, and between ERor = 15% and15%. Linear regression analysis was also performed between L/B and retention ratios and Ki-67 expression.There was a significant increase of the (99m)Tc-(V)DMSA L/B ratio in late images as compared to the early images in group I (P0.05), while in group II it was not significantly increased (P=0.084). (99m)Tc-sestamibi ratios did not demonstrate variability over time in either group (P=0.156 and 0.274, respectively). Significant coefficient correlation was found between the (99m)Tc-(V)DMSA L/B(late) ratios and retention ratios and Ki-67 levels only for group I (r=0.889, P0.001 and r=0.802, P0.01, respectively). The (99m)Tc-(V)DMSA L/B(late) ratios in group I were significantly higher when Ki-673% than when Ki-67or = 3% (P=0.016) but did not differ considerably between ER15% andor = 15% (P=0.732).(99m)Tc-(V)DMSA uptake in UDH correlates with Ki-67 expression. This could prove useful in identifying women with benign but high-risk breast pathologies who might benefit from chemoprophylaxis.

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.

Angiogenesis (as microvascular density—MVD) and vascular endothelial growth factor (VEGF) expression were evaluated by immunohistochemistry in all types of human pre-invasive breast lesion, un-associated with invasive carcinoma, including florid ductal hyperplasia of usual type (FDHUT, 40 cases), atypical ductal hyperplasia (ADH, 10), well-differentiated intraductal carcinoma (WDIC, 16), intermediately differentiated intraductal carcinoma (IDIC, 25), poorly differentiated intraductal carcinoma (PDIC, 20), atypical lobular hyperplasia (ALH, 13), and lobular carcinoma in situ (LCIS, 12). Both parameters were also studied in normal glandular structures obtained from normal breasts or from breasts containing pre-invasive lesions. Increased vascularization was present in all lesion types (MVD mean values (expressed as vessel number/mm2): 115 ± 8 in normal lobules, 146 ± 26 in lesions; p < 0.05) and increased with lesion severity. In ductal lesions, MVDs were significantly higher in PDIC (190 ± 65) and IDIC (167 ± 61) than in FDHUT (123 ± 40) and ADH (122 ± 47); MVD was much higher in PDIC than in WDIC (p < 0.001). WDIC showed peculiar features, with a degree of vascularization closer to hyperplasia than to the other histological types of in situ ductal cancer; this observation is in line with the hypothesis that IDIC and PDIC may originate ‘de novo’, without a mandatory transition through WDIC. LCIS was more vascularized than ALH (168 ± 50 and 125 ± 40, respectively; p < 0.05), showing MVD values similar to those of PDIC and IDIC. The vascularization of normal lobules was constant, regardless of their association with lesions. VEGF expression in normal glandular structures was lower than in lesions, with the highest levels found in ductal lesions when compared with lobular lesions. No correlation was found between VEGF expression and the degree and/or type of vascularization. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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.

Laminin is a glycoprotein of the basement membrane (BM), involved in a variety of normal and pathological cellular events including tumour invasion and metastasis. Cells bind laminin through different types of receptor. The 67-kD laminin receptor (67LR) is a cell-surface protein which binds laminin with high affinity. 67LR expression has been shown to increase in neoplastic cells, compared with normal tissues, and 67LR seems to play an important role during the first steps of neoplastic progression. In this study, 67LR expression was analysed during the morphological phases of breast cancer progression from normal tissue to invasive carcinoma. A total of 506 formalin-fixed, paraffin-embedded normal breast structures and lesions were stained by immunohistochemistry using the MLuC5 monoclonal antibody, which is specific for 67LR. The results show that in normal breast and in any kind of breast lesion, myoepithelial and endothelial cells express 67LR. While 67LR is not seen in the epithelium of normal breast, cysts, adenosis, and benign tumours, it is expressed in the epithelial cells of several hyperplasias and carcinomas in situ, both ductal and lobular, as well as in all invasive carcinomas. The 67LR-positive cell subpopulation expands from hyperplastic lesions to invasive carcinoma, suggesting that 67LR could be related to the induction and progression of breast cancer. © 1997 John Wiley & Sons, Ltd.

The cytogenetic analysis of five mammary epithelial hyperplasias is reported. Only two cases had clonal chromosome alterations. Structural alterations involved chromosomes 1 and 5. Numerical alterations involved chromosomes X, 1, 6, 9, and 19. In four cases, the modal number was in the diploid range, and one case was tetraploid. The study of benign proliferations and their comparison with the chomosome alterations of their malignant counterparts could lead to a better understanding of the genes acting solely in cell proliferation and those that cause these cells to undergo malignant transformation and to become invasive.

A 24-year-old woman, para 2, who was 36 weeks pregnant, presented with massive diffuse enlargement of both breasts, which had progressed since conception (Panel A). There had been no such enlargement during her earlier pregnancies. Multiple cutaneous ulcerations occurred as a result of the rapid enlargement of the breasts over a period of 4 to 5 months. The breasts were normal on ultrasonography. Fine-needle aspiration revealed hyperplasia of the mammary glands that was consistent with pregnancy (Panel B), with no evidence of fibrosis or cancer. Supportive treatment was given until delivery at 38 weeks of gestation. The patient did not . . .

Moderate bilateral enlargement of the breasts is a normal finding during pregnancy and lactation. There is a continuity from this physiological hypertrophy to a massive breast hyperplasia or gigantomastia complicating pregnancy, occurring in about one in 28000 births (Lewison et al, 1960). The physiological breast hypertrophy of pregnancy as well as the rare gigantomastia are bilateral in the vast majority of cases. The presence of tumour should always be suspected in cases of unilateral breast enlargement. We present what we believe is the first description of a massive unilateral breast hyperplasia in pregnancy simulating neoplasm on mammography and ultrasonography.

A cohort study of women with ductal involvement by cells of atypical lobular hyperplasia (DIALH) revealed an incidence of 1.4% in benign biopsy specimens. When combined with diagnostic lobular unit alterations of atypical lobular hyperplasia (ALH), a consequent risk of invasive carcinoma of 6.8 times that in the general population was found. This relative risk for women with ALH and DIALH approaches the risk for lobular carcinoma in situ, whereas the risk for ALH with or without DIALH is 4.3 and the risk for ALH without DIALH is reduced to 2.7. Only definitive changes of DIALH with an insinuated characteristic population of cells between attenuated luminal cells and basement membrane should be so diagnosed. DIALH in association with lobular alterations that are borderline with regard to a diagnosis of lobular carcinoma in situ will increase the certainty that a medically meaningful increased risk for subsequent invasive cancer is indicated.