Elevated EGFR signals in epithelial cells delay mammary gland development and skew organoids away from stem cell signatures
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE149275 | GEO | 2020/08/01
REPOSITORIES: GEO
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2014-11-26 | GSE47375 | GEO
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2010-02-05 | E-GEOD-16380 | biostudies-arrayexpress
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
Project description:CCAAT/enhancer binding protein beta (C/EBPb) is a member of a family of highly conserved transcription factors that regulates numerous genes involved in proliferation and differentiation in a variety of tissues. C/EBPb is deregulated in human breast cancer and germline deletion of this gene results in multiple defects in mammary gland development. We hypothesized that C/EBPb regulates mammary stem cell self-renewal, maintenance and/or differentiation through the regulation of multiple target genes that coordinate mammary gland development. Utilizing both a germline knockout mouse model and a conditional knockout strategy, we demonstrated that mammosphere formation was significantly decreased in C/EBPb-deficient mammary epithelial cells (MECs). The ability of C/EBPb-deleted MECs to regenerate the mammary gland in vivo was severely impaired when transplanted at limiting dilution. Furthermore, serial transplantation of C/EBPb-null mammary tissue resulted in decreased outgrowth potential when compared to wildtype, and an early senescence phenotype. Flow cytometric analysis revealed that C/EBPb-null MECs contain a lower frequency of repopulating stem cells accompanied by an increase in committed, differentiated luminal cells as compared to wildtype. Microarray analysis of stem/progenitor cell populations was performed and revealed an alteration in cell fate specification in C/EBPb-null glands, exemplified by the aberrant expression of basal markers in the luminal cell compartment. Collectively, our studies demonstrate that C/EBPb is a critical regulator of mammary stem cell differentiation, and an important determinant of luminal cell fate specification. Keywords: multiple group comparison
2010-01-28 | GSE16380 | GEO