Expression data from Estrogen Receptor alpha-positive Progesterone Receptor-positive Mammary Tumors in STAT1-/- Mice.
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Szeman Chan
PROVIDER: E-GEOD-31942 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Aged STAT1-/- female mice spontaneously develop ERa+ PR+ mammary tumors that exhibit strikingly similar hormone-sensitivity and -dependency as human ERa+ luminal breast cancers. We used microarray data to compare the genetic relationships between the STAT1-/- mammary tumors and human breast cancers.
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Project description:Conventional transgenic and knockout models do not allow selective introduction of oncogenic alterations into the progenitor population of mammary cells; thus, the role of progenitor cells in mammary tumorigenesis is yet unknown. By generating transgenic mice expressing tva – encoding the receptor for avian leukosis virus subgroup A (ALV/A) – from the Keratin 6a (K6) gene promoter, we found that K6+ mammary cells are bipotential progenitor cells, but not stem cells. These K6+ cells were readily induced to form tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding polyoma middle T antigen. Compared with tumors induced by the same oncogene-expressing virus in transgenic mice expressing tva from the commonly used MMTV LTR or other murine models of breast cancer, tumors in this K6-tva line were unique in that they resemble the normal breast-like subtype of human breast cancer. Consequently, these observations suggest that the cell of origin affects mammary tumor phenotypes. This K6-tva model may be useful for preclinical testing of targeted therapy for normal-like breast cancers in patients. Keywords: Three group comparison We carried out Affymetrix array analysis of five RCAS-PyMT-induced tumors each from K6-tva mice and MMTV-tva mice, as well as five mammary tumors from MMTV-PyMT transgenic mice.
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Project description:While protein arginine methyltransferases (PRMTs) and PRMT-catalyzed protein methylation have been well-known to be involved in a myriad of biological processes, their roles in carcinogenesis, particularly in estrogen receptor alpha (ERa)-positive breast cancers, remain incompletely understood. Here we focused on investigating PRMT4 (also called coactivator associated arginine methyltransferase 1, CARM1) due to its high expression and the associated poor prognosis in ERa-positive breast cancers. We first uncovered the chromatin-binding landscape and transcriptional targets of CARM1 in the presence of estrogen in ERa-positive breast cancer cells employing genomic and transcriptomics approaches. CARM1 was found to be predominantly and specifically recruited to ERa-bound active enhancers and essential for the transcriptional activation of cognate estrogen-induced gene transcriptional activation in response to estrogen. Global mapping of CARM1 substrates revealed that CARM1 methylates a large cohort of proteins with diverse biological functions, including regulation of intracellular estrogen receptor signaling, chromatin organization, chromatin remodeling and others. Intriguingly, a number of proteins were hypermethylated exclusively by CARM1 on a cluster of arginine residues. Exemplified by MED12, hypermethylation of these proteins by CARM1 served as a molecular beacon for recruiting coactivator protein, tudor domain-containing 3 (TDRD3), to ensure the full activation of estrogen/ERa target genes. In consistent with its critical role in estrogen-induced gene transcriptional activation, CARM1 was found to promote cell proliferation of ERa-positive breast cancer cells in vitro and tumor growth in mice. Taken together, our study uncovered a “hypermethylation” strategy utilized by CARM1 in gene transcriptional regulation, and suggested that CARM1 can server as a therapeutic target for breast cancer treatment.
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Project description:The prognosis of a patient with Estrogen Receptor (ER) and/or Progesterone Receptor (PR)-positive breast cancer is highly variable. Therefore, we developed a gene-expression based outcome predictor for ER+ and/or PR+ (i.e. Luminal) breast cancer patients using biological properties of the tumors. First, we identified estrogen-regulated genes using the ER+ MCF-7 breast cancer cell line treated with estrogen. The estrogen-induced gene set was then used to hierarchically cluster a training set of 65 ER+ and/or PR+ tumors into 2 group, which showed survival differences (p=0.0004). Next, supervised analyses based upon these two groups was performed and identified 822 genes that optimally defined these two groups, with the poor prognosis Group IIE tumors showing a proliferation signature and high expression of anti-apoptosis genes and the good outcome Group IE showing the high expression of estrogen and GATA3-induced genes. Centroids were created for each group and applied to ER+ and/or PR+ tumors from three published datasets. For all datasets, Kaplan-Meier survival analyses showed a statistically significant difference in Relapse-Free Survival (and Overall) between Group IE and IIE tumors. Multivariate Cox analysis of the largest test dataset also showed that this predictor was adding independent information. This study provides new biological information concerning differences within Luminal/ER+ breast cancers and a means of predicting long term outcomes in ER+ and/or PR+ breast cancer patients. Keywords: other
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