Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Progesterone promotes immunomodulation and tumor development in the murine mammary gland

ABSTRACT: Clinical studies have linked use of progestins (synthetic progesterone (P4)) to breast cancer risk. However, little is understood regarding the role native P4, signaling through the progesterone receptor (PR), plays in formation of breast tumors. Studies published by our lab highlighted a link between PR and immune signaling pathways, suggesting PR induces PR to repress the interferon signaling pathway. Given these findings, we sought to investigate whether P4/PR drive immunomodulation in the mammary gland and development of mammary gland tumors. We found that mice treated with P4 displayed changes in the mammary gland suggesting inhibited immune response compared to placebo-treated mice. Furthermore, transgenic mice with PR overexpression demonstrated decreased numbers of immune cell populations in their mammary gland, lymph nodes, and spleens. Upon long-term monitoring, we determined that multi-parous PR overexpressing mice developed significantly more mammary gland tumors than control mice. Additionally, tumors of PR overexpressing mice contained fewer infiltrating immune cells. Finally, RNA sequencing analysis of tumor samples revealed that immune-related gene signatures were enriched in tumors of control mice compared to tumors of PR overexpressing mice. Together, these findings provide a novel mechanism behind P4-mediated promotion of mammary gland tumor development and provide rationale to investigate anti-progestin treatment to promote immune-mediated elimination of mammary gland tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE158134 | GEO | 2021/09/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Identification of Murine Uterine Genes Regulated in a Ligand-Dependent Manner by the Progesterone Receptor.

Project description:Progesterone (P4) acting through its cognate receptor, the progesterone receptor (PR), plays an important role in uterine physiology. The PR knockout (PRKO) mouse has demonstrated the importance of the P4-PR axis in the regulation of uterine function. To define the molecular pathways regulated by P4-PR in the mouse uterus, Affymetrix MG U74Av2 oligonucleotide arrays were used to identify alterations in gene expression after acute and chronic P4 treatments. In the analysis, retinoic acid metabolic genes, cytochrome P 450 26a1 (Cyp26a1), alcohol dehydrogenase 5, and aldehyde dehydrogenase 1a1 (Aldh1a1); kallikrein genes, Klk5 and Klk6; and specific transcription factors, GATA-2 and Cited2 [cAMP-corticosterone-binding protein/p300-interacting transactivator with glutamic acid (E) and aspartic acid (D)-rich tail], were validated as regulated by the P4-PR axis. Identification and analysis of these responsive genes will help define the role of PR in regulating uterine biology. Ovariectomized wild-type and progesterone receptor knockout mice were injected with either vehicle or 1 mg/mouse progesterone. The injections were repeated every 12 h, and groups of mice were killed 4 h after the first injection (acute P4 treatment) or 4 h after the fourth injection (chronic P4 treatment).

2012-08-06 | E-GEOD-39920 | biostudies-arrayexpress

Genome-wide Profiling of Progesterone Receptor and GATA2 Binding in the Mouse Uterus [ChIP-Seq]

Project description:Progesterone (P4) signaling through its nuclear transcription factor, the progesterone receptor (PR), is essential for normal uterine function. Although deregulation of PR mediated signaling is known to underscore uterine dysfunction and a number of endometrial pathologies, the early molecular mechanisms of this deregulation are unclear. To address this issue, we have defined the genome-wide PR and GATA2 cistrome in the murine uterus using chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq). In uteri of ovariectomized mice, we identified 6367 PR binding sites in the absence of P4 ligand; however, this number increased at nearly three fold (18,432) following acute P4 exposure. Sequence analysis revealed that approximately 73% of these binding sites contain a progesterone response element (PRE) or a half-site motif recognized by the PR. Many previously identified P4 target genes known to regulate uterine function were found to contain PR binding sites, confirming the validity of our methodology. In addition we identified 46,183 GATA2 binding sites in P4 treatment conditions with 7,954 binding sites overlapping that of the PR.

2012-09-06 | GSE34927 | GEO

Genome-wide Profiling of Progesterone Receptor and GATA2 Binding in the Mouse Uterus [Affymetrix]

2012-09-06 | GSE34902 | GEO

Genome-wide Profiling of Progesterone Receptor and GATA2 Binding in the Mouse Uterus [ChIP-Seq]

2012-09-06 | E-GEOD-34927 | biostudies-arrayexpress

Genome-wide Profiling of Progesterone Receptor and GATA2 Binding in the Mouse Uterus [Affymetrix]

2012-09-06 | E-GEOD-34902 | biostudies-arrayexpress

Progesterone receptor ChIP-seq within the mouse mammary gland

Project description:Progesterone (P) acting through its cognate nuclear receptors (PRs) plays an essential role in driving pregnancy-associated branching morphogenesis of the mammary gland. However, the fundamental mechanisms, including global cistromic and acute genomic transcriptional responses that are required to elicit active branching morphogenesis in response to P, have not been elucidated. We used chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) to identify P-regulated genes that directly recruit PRs in the mouse mammary gland after acute P treatment. Two replicate PR ChIP samples and two replicate input DNA control samples from mouse mammary glands after mice are treated subcutaneously with 17?-Estradiol for 24 hours and then 17?-Estradiol plus Progesterone for 6 hours.

2013-08-27 | E-GEOD-42887 | biostudies-arrayexpress

RNA-Seq of MCF7 intraductal xenografts hormonally treated

Project description:Using a large variety of methods we demostrate that PGR can be a driver of tumor proliferation even in absence of extensive E2. In this specific experiment we treat MCF7 cells intraductally xenografted into the ductal tree of a mouse mammary gland, with estrogen (E2), progesterone (P4) and the combination of the two (E2+P4).

2022-04-05 | GSE192809 | GEO

RNA-Seq of intraductal breast cancer PDX hormonally treated

Project description:Using a large variety of methods we demostrate that PGR can be a driver of tumor proliferation even in absence of high E2. In this specific experiment we treat breast cancer cells intraductally xenografted into the ductal tree of a mouse mammary gland, with estrogen (E2), progesterone (P4) and the combination of the two (E2+P4).

2022-04-05 | GSE192810 | GEO

Differential Roles of ERα and ERβ in Normal and Neoplastic Development in the Mouse Mammary Gland

Project description:The present experiments were performed to determine the roles of estrogen receptors α and β (ERα and ERβ) in normal and neoplastic development in the mouse mammary gland. In wild-type mice, in vivo administration of estradiol (E) + progesterone (P) stimulated mammary ductal growth and alveolar differentiation. Mammary glands from mice in which the ERβ gene has been deleted (βERKO mice) demonstrated normal ductal growth and differentiation in response to E + P. By contrast, mammary glands from mice in which the ERα gene has been deleted (αERKO mice) demonstrated only rudimentary ductal structures that did not differentiate in response to E + P. EGF demonstrates estrogen-like activity in the mammary glands of αERKO mice: treatment of αERKO mice with EGF + P (without E) supported normal mammary gland development, induced expression of progesterone receptor (PR), and increased levels of G- protein-coupled receptor (GPR30) protein. Mammary gland development in βERKO mice treated with EGF + P was comparable to that of wild-type mice receiving EGF + P; EGF had no statistically significant effects on the induction of PR or expression of GPR30 in mammary glands harvested from either wild-type mice or βERKO mice. In vitro exposure of mammary glands to 7,12-dimethylbenz[a]anthracene (DMBA) induced preneoplastic mammary alveolar lesions (MAL) in glands from wild-type mice and βERKO mice, but failed to induce MAL in mammary glands from αERKO mice. Microarray analysis of DMBA-treated mammary glands identified 28 functional pathways whose expression was significantly different in αERKO mice versus both βERKO and wild-type mice; key functions that were differentially expressed in αERKO mice included cell division, cell proliferation, and apoptosis. The data demonstrate distinct roles for ERα and ERβ in normal and neoplastic development in the mouse mammary gland, and suggest that EGF can mimic the ERα-mediated effects of E in this organ.

2014-10-18 | GSE62451 | GEO

BK5.ATF3-induced mammary tumors compared to normal mammary glands

Project description:Transcriptional profiling of mammary tumors that occur in parous, BK5.ATF3 mice, compared to normal mammary tissue

2021-03-23 | GSE162793 | GEO