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RB pathway deregulation promotes invasion and disease progression in a mouse model of MYC-overexpressing mammary tumorigenesis

ABSTRACT: Breast cancer is a highly heterogeneous disease that is categorized into distinct tumor subtypes based on specific molecular attributes, which ultimately influence therapeutic options. Unlike ER+ and/or HER2+ cancers that are subject to specific targeted therapies, triple negative breast cancers (TNBCs) do not express these receptors, which leaves patients with limited treatment options. Thus, significant focus has been placed on identifying molecular attributes of basal-like disease that could be used to develop and/or direct novel treatment regimens. Activation of MYC signaling and inactivation of the RB-pathway are frequent events in many types of human cancers. These pathways influence many biological processes, such as cell proliferation, that contribute to the aggressiveness and therapeutic response of tumors. The current study examines the interaction of the MYC and RB pathways in mammary epithelial cell tumorigenesis. Mouse mammary epithelial cells were isolated and sub-cultured. Adenoviral expression of Cre-recombinase was used to delete the RB and/or p53 genes, and retrovirus was used to achieve MYC overexpression (OE). Proliferating cells were harvested for each condition, and RNA was isolated for analyses.

ORGANISM(S): Mus musculus

SUBMITTER: Adam Ertel

PROVIDER: E-GEOD-40545 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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RB pathway deregulation promotes invasion and disease progression in a mouse model of MYC-overexpressing mammary tumorigenesis

Project description:Breast cancer is a highly heterogeneous disease that is categorized into distinct tumor subtypes based on specific molecular attributes, which ultimately influence therapeutic options. Unlike ER+ and/or HER2+ cancers that are subject to specific targeted therapies, triple negative breast cancers (TNBCs) do not express these receptors, which leaves patients with limited treatment options. Thus, significant focus has been placed on identifying molecular attributes of basal-like disease that could be used to develop and/or direct novel treatment regimens. Activation of MYC signaling and inactivation of the RB-pathway are frequent events in many types of human cancers. These pathways influence many biological processes, such as cell proliferation, that contribute to the aggressiveness and therapeutic response of tumors. The current study examines the interaction of the MYC and RB pathways in mammary epithelial cell tumorigenesis.

2013-08-01 | GSE40545 | GEO

Expression data MCF10A/ErbB2 RB-proficient and RB-deficient cells cultured in 3-D cell culture

Project description:Gene expression analysis for structural components in Rb-deficient and RB-proficient ErbB2-overexpressing immortalized breast cell line using 3-D cell culture model to analyze structural and organizational changes of epithelial cells. Cells were cultured in a reconstituted membrane for 7 days. Cells were extracted with the use RNA-STAT-60 method.

2013-03-01 | E-GEOD-36425 | biostudies-arrayexpress

Cooperativity of Rb, Brca1, and p53 and malignant breast cancer evolution (MFT121 p53f/f Brca1f/f)

Project description:Breast cancers that are “triple-negative” for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Gene expression analyses demonstrate that the tumors share attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader, triple-negative class defined by clinical markers. These studies establish a unique animal model of aggressive forms of breast cancer for which there are no effective, targeted treatments. Rb, p53, and Brca1 are associated with inherited forms of cancer, but defects in these pathways are also found together in a subset of breast cancer patients without a family history of the disease. Simultaneous inactivation of all three pathways causes more aggressive disease than do pair-wise combinations, indicating that the pathways play non-overlapping roles in tumor prevention. We investigated the effect of perturbation of Rb family pathways, p53, and/or Brca1 in mouse mammary epithelium. Eighteen tumors were compared to normal spleen DNA.

2012-09-18 | E-GEOD-40925 | biostudies-arrayexpress

Heterogeneity in MYC-Induced Mammary Tumors Determines Outcomes Following Loss of Myc Activity

Project description:We used microarrays to compare gene expression profiles between mouse mammary tumors initiated by Myc to those that have escaped Myc oncogene dependence. We collected tumor biopsies of Myc-initiated tumors and samples of tumors that persisted or recurred after Myc withdrawal. RNA was extracted from these tumors and hybridized to microarrays.

2010-07-08 | E-GEOD-22406 | biostudies-arrayexpress

Cooperativity of Rb, Brca1, and p53 and malignant breast cancer evolution

Project description:The dire need for more effective treatments for clinically aggressive breast cancers has motivated intensive investigations into their cellular and molecular etiology. Breast cancers that are “triple-negative” for the clinical markers, ESR1, PGR, and HER2, typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency, and predisposes highly penetrant, metastatic, adenocarcinomas. These tumors are poorly differentiated with histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Transcriptomic analyses demonstrated that the tumors shared attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader triple-negative category defined by clinical markers. Ex vivo tumorsphere formation, which was suppressed by Notch and Wnt pathway inhibition, and tumor antigen profiles and are consistent with enrichment of stem-like and luminal progenitor cells among these tumors. These studies establish a novel mouse model of malignant breast cancer based on events in the human disease and underscore the non-reciprocal requirements of three canonical tumor suppressor pathways in breast cancer evolution. Morphogenetic pathways may provide additional avenues for targeted therapeutic intervention. Gene expression analysis of mouse mammary tumors with perturbation of Rb family pathways, p53, and/or Brca1 are compared to other mouse model tumors (n=152)

2011-12-17 | E-GEOD-34479 | biostudies-arrayexpress

Cooperativity of Rb, Brca1, and p53 and malignant breast cancer evolution (MFT121 p53f/f Brca1f/f)

2012-09-18 | GSE40925 | GEO

Cooperativity of Rb, Brca1, and p53 and malignant breast cancer evolution

2011-12-17 | GSE34479 | GEO

Prolactin-inducible Stat5a-mediated and Stat5b-mediated gene profiles

Project description:Stat5a and Stat5b proteins are highly homologous with greater than 90% amino acid identity and share binding to the palindromic Stat5 consensus sequence, TTCNNNGAA, but individual roles of each transcription factor in breast cancer have not been thoroughly evaluated. To determine the degree of similarity between transcripts modulated by Stat5a and Stat5b proteins in human breast cancer, we utilized genome-wide transcript profiling to identify genes regulated specifically by Stat5a or Stat5b in response to prolactin. Stat5a or Stat5b was transiently overexpressed using adenoviral gene delivery in MCF7 breast cancer cells followed 16 hr serum starvation and a brief 4 hr exposure to 10nM human prolactin to identify immediate-early transcripts modulated by each transcription factor. Basal activation of Stat5a or Stat5b was not present in cells not stimulated with prolactin. mRNA from each condition was harvested and validated using the Agilent bioanalyzer. cDNA was generated and genome-wide transcript profiling was performed in triplicate using the Affymetrix HuGene 1.0 ST array.

2012-08-29 | E-GEOD-37781 | biostudies-arrayexpress

Cyclin D1 determines estrogen dependent signaling in human breast cancer cell line MCF7

Project description:The CCND1 gene, which is frequently overexpressed in cancers, encodes the regulatory subunit of a holoenzyme that phosphorylates the retinoblastoma protein (pRb). It is known that cyclin D1 regulates ERM-NM-1 transactivation using heterologous reporter systems, the significance of this observation to E2 dependent gene activation is unknow. E2 stimulated MCF7 cells treated with cyclin D1 siRNA in order to analyze the genes regulated by estradiol in a cyclin D1 dependent manner. Hormone deprived MCF7 cells were treated with cyclin D1 siRNA or control siRNA and stimulated with E2 or vehicle Four separate 10cm plates of MCF7 cells treated with control siRNA were compared to four 10cm plates of MCF7 cells treated with cyclin D1 siRNA. 2 plates in each group treated with vehicle and two plates treated with E2.

2013-07-18 | E-GEOD-48989 | biostudies-arrayexpress

Genomic profiles of mouse liver tissue harboring deletion of RB and/or p53, untreated or post-hepatocarcinogen treatment [expression data]

Project description:The retinoblastoma (RB) and p53 tumor suppressors are critical regulators of the cell cycle with profound impact on both normal cell biology and disease etiology. In the context of human cancers, compound inactivation of RB and p53 is a frequent occurrence; however, the cooperation of these tumor suppressors in driving tumorigenesis has proven to be intricate and dependent on both the tissue and type of cancer. Hepatocellular carcinoma (HCC) is a highly complex disease characterized by numerous molecular abnormalities (e.g. p53, RB, TGFβ) and chromosomal aberrations associated with environmental factors (e.g. Hepatitis B/C Virus, Aflatoxin B1). Despite extensive research, how each of these facets of disease development cooperates in promoting tumorigenesis is ultimately unknown. In the current study, we present a mouse model of liver tumorigenesis, in which the impact of RB and p53 loss is modified by the tissue environment. While loss of RB and p53 promotes deregulation of transcriptional programs associated with advanced disease, these changes are not sufficient to drive spontaneous tumorigenesis in the liver. However, in response to carcinogen-induced damage, distinct and cooperative roles of RB and p53 are revealed, which critically impact cell cycle control, checkpoint response, genome stability, and ultimately tumor development. Mice that are transgenic for Cre recombinase under the albumin promoter and harboring loxP sites within the Rb and/or p53 genes. For gene expression microarray analysis, mice were aged to 14 days, and treated for 24 hours with diethylnitrosamine (DEN) or saline as a control. For CGH analysis, mice were aged to 6 months post-DEN treatment. Liver tissue was obtained from dissected tumors and compared to normal liver tissue of 6-month old, saline-treated littermates. CGH analysis includes 5 individual tumor samples and 2 control samples (each consisting of a pool of 3 normal mouse liver DNA).

2011-09-19 | E-GEOD-29846 | biostudies-arrayexpress

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