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Bone morphogenetic protein-2 (BMP2) and estradiol-17β (E2)-induced changes in ovarian transcriptome during primordial follicle formation in the mouse ovary

ABSTRACT: Estradiol-17β (E2) has been shown to promote primordial follicle (PF) formation and to involve BMP2 as a downstream effector to promote PF in the hamsters. However, the molecular mechanism whereby these factors regulate ovarian somatic cells to pre-granulosa cells (preGC) transition leading to PF formation remains unclear. The objective of this study was to determine whether BMP2 and/or E2 would regulate the expression of specific ovarian transcriptome during preGC transition and PF formation in the mouse ovary. BMP2 mRNA level increased during the period of PF formation with concurrent presence of BMP2 protein in ovarian somatic cells. E2 but not BMP2 exposure led to increased expression of ovarian BMP2 mRNA, and the effect of E2 could not be suppressed by LDN 193189 (LDN). Either BMP2 or E2 stimulated PF formation without inducing apoptosis. RNAseq analysis of ovaries exposed to exogenous BMP2 or E2 revealed differential expression of several thousand genes. Most of the differentially expressed genes (DEG), which were common between BMP2 or E2 treatment demonstrated concordant changes, reinforcing the idea of cooperativity between E2 and BMP2 during PF formation. Further, we have Identified E2, in cooperation with BMP2, could affect the expression of three major transcription factors GATA2, GATA4 and EGR2 and one serine protease, hepsin in preGC during PF formation. Taken together, results of this study suggest that E2 and BMP2 may regulate ovarian gene expression that promote somatic cells to preGC transition and PF formation in the mouse ovary.

ORGANISM(S): Mus musculus

PROVIDER: GSE197122 | GEO | 2022/05/31

REPOSITORIES: GEO

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Project description:MCF-7:PF is a a new in vitro model of antihormone resistant breast cancer that exhibits the characteristics of acquired tamoxifen resistance in vivo. It is well known that estrogen (E2) induces apoptosis in long-term estrogen-deprived breast cancer cells, MCF-7:5C (PubMed References PMID:15862958, PMID:16333030). MCF-7:PF was derived from MCF-7:5C through inhibition of c-Src, which blocks E2-induced apoptosis, coverts E2 responses from apoptosis to proliferation. MCF-7:PF cell growth is stimulated by E2 and SERMS in an ERα-dependent manner. Abstract: A c-Src inhibitor blocks estrogen (E2)-induced stress and converts E2 responses from inducing apoptosis to stimulating growth in E2-deprived breast cancer cells. A resulting cell line, MCF-7:PF, is reprogrammed with features of functional estrogen receptor (ER) and over-expression of insulin-like growth factor-1 receptor beta (IGF-1Rβ). We addressed the question of whether the antiestrogenic selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E2-stimulated growth in MCF-7:PF cells. Unexpectedly, 4-OHT stimulated cell growth in an ER-dependent manner. However, unlike E2, 4-OHT suppressed classic ER-target genes as does the pure antiestrogen ICI 182,780, even during growth stimulation. Chromatin-immunoprecipitation (ChIP) assay indicated that 4-OHT did not recruit ER or nuclear receptor coactivator 3 (SRC3) to the promoter of ER-target gene, pS2. Paradoxically, 4-OHT reduced total IGF-1Rβ but increased phosphorylation of IGF-1Rβ, which was responsible for the activation of the phosphatidylinositol-3 kinases (PI3K)/Akt signaling pathway. Mechanistic studies revealed that 4-OHT rapidly activated the non-genomic pathway through ER, but other membrane-associated proteins such as IGF-1Rβ and c-Src participated. Furthermore, 4-OHT was more potent than E2 to up-regulate membrane remodeling molecules and activated focal adhesion molecules to promote cell growth. Therefore, disruption of membrane-associated signaling completely abolished 4-OHT-stimulated cell growth, but not E2-stimulated cell growth. Despite continued suppression of classic ER-target genes, 4-OHT activated the complex network of cytoskeleton remodeling and extracellular matrix-related signaling which facilitated 4-OHT-stimulated cell growth. This study is the first to recapitulate a cellular model in vitro of acquired tamoxifen (TAM) resistance developed in athymic mice in vivo.

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Bone morphogenetic protein-2 (BMP2) and estradiol-17β (E2)-induced changes in ovarian transcriptome during primordial follicle formation in the mouse ovary

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