A mouse model for Luminal epithelial like ER positive subtype of human breast cancer

Kumar, MJ Mahesh; Ponvijay, KS; Nandhini, R.; Nagarajan, RS; Jose, Jedy; Srinivas, G.; Nagarajan, Priyadharsini; Venkatesan, R.; Kumar, Kishor; Singh, Shruti

doi:10.1186/1471-2407-7-180

Cited by 10 publications

(11 citation statements)

References 21 publications

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“…Abundant research has revealed that hormone receptor (i.e., ER) status is one of the most important features of BRCA [36,37]. Epidemiological research has shown that about 70% of BRCA patients are [38]. Nevertheless, ER-positive BRCA still constitutes a more heterogeneous group for diagnosis and treatment [39,40].…”

Section: Discussionmentioning

confidence: 99%

Methylome and transcriptome analyses reveal insights into the epigenetic basis for the good survival of hypomethylated ER-positive breast cancer subtype

Chen

Zhang

et al. 2020

Clin Epigenet

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Background: Breast cancer (BRCA) is a heterogeneous disease, characterized by different histopathological and clinical features and responses to various therapeutic measures. Despite the research progress of DNA methylation in classification and diagnosis of BRCA and the close relationship between DNA methylation and hormone receptor status, especially estrogen receptor (ER), the epigenetic mechanisms in various BRCA subtypes and the biomarkers associated with diagnostic characteristics of patients under specific hormone receptor status remain elusive. Results: In this study, we collected and analyzed methylation data from 785 invasive BRCA and 98 normal breast tissue samples from The Cancer Genome Atlas (TCGA) database. Consensus classification analysis revealed that ERpositive BRCA samples were constitutive of two distinct methylation subgroups; with the hypomethylated subgroup showing good survival probability. This finding was further supported by another cohort of ER-positive BRCA containing 30 subjects. Additionally, we identified 977 hypomethylated CpG loci showing significant associations with good survival probability in ER-positive BRCA. Genes with these loci were enriched in cancerrelated pathways (e.g., Wnt signaling pathway). Among them, the upregulated 47 genes were also in line with good survival probability of ER-positive BRCA, while they showed significantly negative correlations between their expression and methylation level of certain hypomethylated loci. Functional assay in numerous literatures provided further evidences supporting that some of the loci have close links with the modulation of tumor-suppressive mechanisms via regulation gene transcription (e.g., SFRP1 and WIF1). Conclusions: Our study identified a hypomethylated ER-positive BRCA subtype. Notably, this subgroup presented the best survival probability compared with the hypermethylated ER-positive and hypomethylated ER-negative BRCA subtypes. Specifically, we found that certain upregulated genes (e.g., SFRP1 and WIF1) have great potential to suppress the progression of ER-positive BRCA, concurrently exist negative correlations between their expression and methylation of corresponding hypomethylated CpG loci. Therefore, our study indicates that different epigenetic mechanisms likely exist in ER-positive BRCA and provides novel clinical biomarkers specific to ER-positive BRCA diagnosis and therapy.

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Section: Discussionmentioning

confidence: 99%

Methylome and transcriptome analyses reveal insights into the epigenetic basis for the good survival of hypomethylated ER-positive breast cancer subtype

Chen

Zhang

et al. 2020

Clin Epigenet

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“…About one million women worldwide are diagnosed with BC every year (1,2). So it is very important to prevent tumorigenesis and treat cancer.…”

Section: Introductionmentioning

confidence: 99%

A model of spontaneous mouse mammary tumor for human estrogen receptor- and progesterone receptor-negative breast cancer

Zheng

Zhou²,

Meng

et al. 2014

International Journal of Oncology

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Breast cancer (BC) is the most frequently malignancy in women. Therefore, establishment of an animal model for the development of preventative measures and effective treatment for tumors is required. A novel heterogeneous spontaneous mammary tumor animal model of Kunming mice was generated. The purpose of this study was to characterize the spontaneous mammary tumor model. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular stroma, adjacent dermis and muscle tissue. Metastatic spread through blood vessel into liver and lungs was observed by hematoxylin eosin staining. No estrogen receptor (ER) or progesterone receptor (PR) immunoreactivity was detected in their associated malignant tumors, human epidermal growth factor receptor-2 (HER-2) protein weak expression was found by immunohistochemistry. High expression of vascular endothelial growth factor (VEGF), moderate or high expression of c-Myc and cyclin D1 were observed in tumor sections at different stages (2, 4, 6 and 8 weeks after cancer being found) when compared with that of the normal mammary glands. The result showed that the model is of an invasive ductal carcinoma. Remarkably in the mouse model, ER and PR-negative and HER2 weak positivity are observed. The high or moderate expressions of breast cancer markers (VEGF, c-Myc and cyclin D1) in mammary cancer tissue change at different stages. To our knowledge, this is the first report of a spontaneous mammary model displaying colony-strain, outbred mice. This model will be an attractive tool to understand the biology of anti-hormonal breast cancer in women.

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“…Although not deliberately genetically engineered, brother-sister matings of heterozygous NIH nude mice resulted in development of a line of mice with high serum estrogen levels in which 62% of females develop ERα positive metastatic mammary cancers by a mean age of seven months (Kumar, et al 2007) (Table 1E). Mammary adenocarcinomas appear only in breeding females.…”

Section: Spontaneous Er+ Mammary Cancer Nude Mouse Modelmentioning

confidence: 99%

“…There is a strong need for ER+ models that reliably develop metastatic disease. Further characterization of the model developed in nude mice (Kumar et al 2007) is required before it can be effectively used for experiments that might address the pathophysiology of ER+ metastatic disease. Another approach to developing more sophisticated models reflective of individual ER+ breast cancer sub-types will be to combine transgenic Esr1 expression with other genetic manipulations as was accomplished for both TAg expression and loss of Brca1/p53 .…”

Section: Future Directionsmentioning

confidence: 99%

Genetically engineered ERα-positive breast cancer mouse models

Dabydeen¹,

Furth²

2014

Endocrine-Related Cancer

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The majority of human breast cancers are ER+ but this has proven challenging to model in genetically engineered mice. This review summarizes information on twenty-one mouse models that develop ER+ mammary cancer. Where available, information on cancer pathology and gene expression profiles is referenced to assist in understanding which histological subtype of ER+ human cancer each model might represent. Esr1, Ccdn1, prolactin, TGFα, AIB1, Espl1, and Wnt1 over-expression, Pik3ca gain of function, as well as loss of p53 or loss of Stat1 are associated with ER+ mammary cancer. Treatment with the PPARγ agonist efatutazone in a mouse with Brca1 and p53 deficiency and DMBA exposure in combination with an activated myristoylated form of AKT1 also induce ER+ mammary cancer. A spontaneous mutant in nude mice that develops metastatic ER+ mammary cancer is included. Age of cancer development ranges from three to 26 months and the percentages of cancers that are ER+ vary from 21% to 100%. Not all models are characterized as to their estrogen dependency and/or response to anti-hormonal therapy. Strain backgrounds include C57Bl/6, FVB, BALB/c, 129S6/SvEv, CB6F1 and NIH nude. Most models have only been studied on one strain background. In summary while a range of models is available for studies of pathogenesis and therapy of ER+ breast cancers, many could benefit from further characterization and opportunity for development of new models remains.

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A mouse model for Luminal epithelial like ER positive subtype of human breast cancer

Abstract: Background: Generation of novel spontaneous ER positive mammary tumor animal model from heterozygous NIH nude mice.

Cited by 10 publications

References 21 publications

Methylome and transcriptome analyses reveal insights into the epigenetic basis for the good survival of hypomethylated ER-positive breast cancer subtype

Methylome and transcriptome analyses reveal insights into the epigenetic basis for the good survival of hypomethylated ER-positive breast cancer subtype

A model of spontaneous mouse mammary tumor for human estrogen receptor- and progesterone receptor-negative breast cancer

Genetically engineered ERα-positive breast cancer mouse models

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