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Cell density, Her2 and progesterone signaling regulate dissemination of breast cancer cells [Gene expression]

ABSTRACT: Disseminated breast cancer cells display genotypes disparate from the predominant clone of the primary tumor before manifestation of metastasis, suggesting that cancer cell dissemination occurs preferentially early; however, the underlying molecular mechanisms are unknown. Investigating metastasis in a Her2-driven mouse model, we found that the progesterone-induced paracrine cytokines Wnt4 and Rankl induced migration and early dissemination shortly after Her2 activation. Once tumorigenic growth was established, progesterone receptor (PgR) expression was lost and Wnt4/Rankl induced proliferation. The altered response from migration to proliferation was determined by cell density involving miRNA-regulated PgR expression and was reversible. Cells from early, low-density lesions displayed more functional stemness traits than cells from dense, advanced tumors, migrated more and founded significantly more metastases. The data suggest that many metastases are derived from early-disseminated cancer cells, implying that our concepts for systemic therapy need to be revised.

ORGANISM(S): Mus musculus

PROVIDER: GSE68681 | GEO | 2016/12/08

SECONDARY ACCESSION(S): PRJNA283390

REPOSITORIES: GEO

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Cell density, Her2 and progesterone signaling regulate dissemination of breast cancer cells [miRNA-Seq]

Project description:Disseminated breast cancer cells display genotypes disparate from the predominant clone of the primary tumor before manifestation of metastasis, suggesting that cancer cell dissemination occurs preferentially early; however, the underlying molecular mechanisms are unknown. Investigating metastasis in a Her2-driven mouse model, we found that the progesterone-induced paracrine cytokines Wnt4 and Rankl induced migration and early dissemination shortly after Her2 activation. Once tumorigenic growth was established, progesterone receptor (PgR) expression was lost and Wnt4/Rankl induced proliferation. The altered response from migration to proliferation was determined by cell density involving miRNA-regulated PgR expression and was reversible. Cells from early, low-density lesions displayed more functional stemness traits than cells from dense, advanced tumors, migrated more and founded significantly more metastases. The data suggest that many metastases are derived from early-disseminated cancer cells, implying that our concepts for systemic therapy need to be revised.

2016-12-08 | GSE68682 | GEO

Expression data from progesterone receptor knockout versus heterozygous mouse oviducts

Project description:The oviducts play a critical role in gamete and embryo transport, as well as supporting fertilization and early embryo development. Progesterone receptor (PGR) is a transcription factor highly expressed in oviductal cells, while it’s activating ligand, progesterone (P4), surges to peak levels as ovulation approaches. P4 is known to regulate oviduct cilia beating and muscular contractions in vitro, but how PGR may mediate this in vivo is poorly understood. We used PGR-knockout (PRKO) mice to determine how PGR regulates oviductal function during the periovulatory period, in particular oviductal transport and embryo support. We used microarrays to identify putative PGR-regulated genes in the oviduct during the periovulatory period, a time when the oviduct is preparing to receive the newly-ovulated COC.

2014-06-16 | GSE51499 | GEO

Transcriptomic profiles of myometrial PGR deficient and control mouse uteri at gestation day 13

Project description:Progesterone signaling is crucial for pregnancy. To investigate the role of myometrial progesterone receptor in support of pregnancy, genome-wide gene expression profiles of pregnant uterine tissues from myometrial PGR knockout and control mice were profiled by RNAseq. The transcriptomic alterations in response to PGR loss permit identification of the underlying molecular mechanisms by which progesterone and PGR control myometrial homeostasis for pregnancy.

2022-09-21 | GSE199101 | GEO

Transcriptomic profiles of myometrial PGR deficient and control mouse uteri at pseudopregnancy day 6

2022-09-21 | GSE207134 | GEO

Genome-wide binding sites of Progesterone receptor (PGR) isoforms PGR-A and PGR-B during differentiation of human endometrial stromal cells

Project description:We report the genome-wide binding sites of PGR-A and PGR-B at 2h of in vitro differentiation of human endometrial stromal cells that express either PGR-A or PGR-B. Progesterone, acting through the progesterone receptors (PGRs), is one of the most critical regulators of endometrial differentiation, known as decidualization, which is a key step toward the establishment of pregnancy. Yet a long-standing unresolved issue in uterine biology is the precise roles played by the major PGR isoforms, PGR-A and PGR-B, during decidualization in the human. Our approach, expressing PGR-A and PGR-B individually after silencing endogenous PGRs in human endometrial stromal cells (HESC), enabled the analysis of the roles of these isoforms separately as well as jointly by ChIP-seq and gene-expression analysis. In order to study the cistromes of PGR-A and PGR-B at 2h of in vitro differentiation of human endometrial stromal cells, we generated primary cultures of human endometrial stromal cells expressing flag tagged PGR-A and PGR-B individually after silencing endogenous PGRs. Input DNA was used as the reference sample.

2015-04-27 | E-GEOD-62475 | biostudies-arrayexpress

KrM-CM-<ppel-like Factor 9 and Progesterone Receptor Co-Regulation of Decidualizing Endometrial Stromal Cells: Implications for its Loss in the Pathogenesis of Endometriosis

Project description:Endometriosis is characterized by progesterone resistance and is associated with infertility. KrM-CM-<ppel-like Factor 9 (KLF9) is a progesterone receptor (PGR)-interacting protein, and mice null for Klf9 are subfertile. Whether loss of KLF9 contributes to progesterone resistance of eutopic endometrium of women with endometriosis is unclear. The aim of this study was to investigate KLF9 and PGR co-regulation of human endometrial stromal cell (HESC) transcriptome network. Microarray gene expression analysis was conducted in decidualizing HESC by silencing the expression of KLF9 and PGR, alone or in combination by a siRNA approach, to identify additional KLF9 and PGR co-regulated genes and signaling networks/pathways. HESC also treated with 8-bromo-cAMP, 17M-CM-^_-estradiol, and medroxyprogesterone acetate (cAME) to mimic stromal progression from a proliferative to a differentiated state.

2012-04-03 | E-GEOD-31683 | biostudies-arrayexpress

Progesterone Receptor A Isoform Specific ChIP-Seq

Project description:Chromatin immunoprecipitation for the progesterone receptor (PGR) and sequencing was performed on Pgrcre/-mPRALsL/+ mice. These mice exhibit no endogenous PGR expression, yet exhibit constitutive expression of the PGR-A isoform in PGR positive tissues due to the presence of a conditional expression allele. Mice were ovariectomized, rested for two weeks, and treated with progesterone for 1 hour before harvesting and freezing whole uterine tissue.

2019-08-29 | GSE86314 | GEO

Myometrial Progesterone Receptor Isoform B Regulates the Phospholipase C Pathway and Suppresses Uterine Contractility

Project description:Uterine contractile dysfunction leads to pregnancy complications such as preterm birth and labor dystocia. Progesterone is necessary to suppress uterine contractions to prevent premature labor. As humans maintain high levels of progesterone throughout parturition, a functional progesterone withdrawal hypothesis suggests that relative levels of myometrial progesterone receptor isoforms PGR-A and PGR-B switch at parturition, where PGR-B promotes a relaxed state and PGR-A result in increased uterine contractility. Our objective is to determine the effects of altered levels of PGR-B and PGR-A in the mouse myometrium on pregnancy and parturition using transgenic mouse models in which the relative levels of these isoforms are altered specifically in the myometrium. Overexpression of PGR-B is associated with a markedly increased gestational length compared to control mice. In both ex vivo and in vivo experiments, myometrium of PGR-B overexpressing mice have prolonged labor, a significant decrease in uterine contractility, and a high incidence of labor dystocia. Conversely, overexpression of PGR-A is associated with an increase in uterine contractility without a change in gestational length. Uterine RNAseq at mid-pregnancy identified isoform-specific downstream targets and genes that were commonly regulated by both PGR isoforms. Gene signature analyses further revealed that PGR-B promotes muscle relaxation and that PGR-A is pro-inflammation. High levels of PGR-B manifest a genetic profile of a blunted phospholipase C pathway that mediates oxytocin and angiotensin II induced muscle contraction. These findings provided in vivo support that PGR isoform levels determine distinct transcriptomic landscapes and pathways in myometrial function and labor.

2021-02-24 | GSE146634 | GEO

DNA methylome regulation by progesterone receptor in primary leiomyoma cells

Project description:Uterine leiomyomas (LM) affect up to 80% of all reproductive-age women. LM growth requires progesterone, progesterone receptor (PGR), and the maintenance and proliferation of a small (5%) stem cell population. Stem cell activation and differentiation are driven by DNA methylation and nuclear hormone receptor action, but crosstalk between these mechanisms remains unclear. We performed an integrated analysis of the transcriptome and epigenetic landscape of LM cells at three differentiation stages and the PGR cistrome of whole LM tissue. The PGR-deficient stem cell population harbored a unique methylation landscape, with hypermethylation at the PGR gene locus and PGR-binding regions, which suppressed stem cell responsiveness to progesterone. The DNA methylation inhibitor 5’-Aza upregulated the expression of PGR and its target genes by stimulating PGR recruitment to the targeted gene loci, and significantly depleted the LM stem cell population and its tumor-initiating capacity. We herein provided mechanistic insights via therapeutically accelerating the stem cell differentiation process of a hormone-sensitive tumor.

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Genome-wide transcriptome profiling of primary human uterine leiomyoma cell populations

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