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Singleminded-2s (Sim2s) promotes delayed Involution of the Mouse Mammary Gland through suppression of Stat3 and NFkB

ABSTRACT: Post-lactational involution of the mammary gland provides a unique model to study breast cancer susceptibility and metastasis. We have shown that the short isoform of Singleminded-2 (Sim2s), a bHLH/PAS transcription factor, plays a role in promoting lactogenic differentiation, as well as in maintaining mammary epithelial differentiation and malignancy. Sim2s is dynamically expressed during mammary gland development, with expression peaking during lactation, and decreasing in early involution. To determine the role of Sim2s in involution, we used transgenic mice expressing Sim2s under the mouse mammary tumor virus (MMTV-Sim2s) promoter. Over-expression of Sim2s in the mouse mammary gland resulted in delayed involution, indicated by a lower proportion of cleaved caspase-3 positive cells and slower re-establishment of the mammary fat pad. Immunohistochemical and quantitative RNA analysis showed a decrease in apoptotic markers and inflammatory response genes, and an increase in anti-apoptotic genes, which were accompanied by inhibition of signal transducer and activator of transcription 3 (Stat3) activity. Microarray analysis confirmed that genes in the Stat3 signaling pathway were repressed by Sim2s expression, along with NFκB and other key pathways involved in mammary gland development. Multiparous MMTV-Sim2s females displayed a more differentiated phenotype compared to wild-type controls, characterized by enhanced β-casein expression and alveolar structures. Together, these results suggest a role for Sim2s in the normal involuting gland, and identify potential down-stream pathways regulated by Sim2s.

ORGANISM(S): Mus musculus

PROVIDER: GSE27012 | GEO | 2011/02/03

SECONDARY ACCESSION(S): PRJNA137599

REPOSITORIES: GEO

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Singleminded-2s (Sim2s) promotes delayed Involution of the Mouse Mammary Gland through suppression of Stat3 and NFkB

Project description:Post-lactational involution of the mammary gland provides a unique model to study breast cancer susceptibility and metastasis. We have shown that the short isoform of Singleminded-2 (Sim2s), a bHLH/PAS transcription factor, plays a role in promoting lactogenic differentiation, as well as in maintaining mammary epithelial differentiation and malignancy. Sim2s is dynamically expressed during mammary gland development, with expression peaking during lactation, and decreasing in early involution. To determine the role of Sim2s in involution, we used transgenic mice expressing Sim2s under the mouse mammary tumor virus (MMTV-Sim2s) promoter. Over-expression of Sim2s in the mouse mammary gland resulted in delayed involution, indicated by a lower proportion of cleaved caspase-3 positive cells and slower re-establishment of the mammary fat pad. Immunohistochemical and quantitative RNA analysis showed a decrease in apoptotic markers and inflammatory response genes, and an increase in anti-apoptotic genes, which were accompanied by inhibition of signal transducer and activator of transcription 3 (Stat3) activity. Microarray analysis confirmed that genes in the Stat3 signaling pathway were repressed by Sim2s expression, along with NFκB and other key pathways involved in mammary gland development. Multiparous MMTV-Sim2s females displayed a more differentiated phenotype compared to wild-type controls, characterized by enhanced β-casein expression and alveolar structures. Together, these results suggest a role for Sim2s in the normal involuting gland, and identify potential down-stream pathways regulated by Sim2s. Gene expression was measured in 6 mammary gland samples using CodeLink Mouse Whole Genome microarrays. 3 samples were from wild-type mice harvested at 72 hours post weaning and 3 samples were MMTV-Sim2s mice harvested at 72 hours post weaning.

2011-02-03 | E-GEOD-27012 | biostudies-arrayexpress

Efficient Mammary Gland Involution Requires c-Jun N-terminal kinase

Project description:Involution returns the lactating mammary gland to a quiescent state after weaning. The mechanism of involution involves collapse of the mammary epithelial cell compartment. To test whether the cJUN NH2-terminal kinase (JNK) signal transduction pathway contributes to involution, we established mice with JNK deficiency in the mammary epithelium. We found that JNK is required for efficient involution. JNK deficiency did not alter the STAT3/5 or SMAD2/3 signaling pathways that have been previously implicated in this process. Nevertheless, JNK promotes the expression of genes that drive involution, including matrix metalloproteases, cathepsins, and BH3-only proteins. These data demonstrate that JNK has a key role in mammary gland involution post lactation.

2018-03-09 | GSE89495 | GEO

Intracellular Calcium links Milk Stasis to Lysosome Dependent Cell Death during Early Mammary Gland Involution

Project description:Involution of the mammary gland after lactation is a dramatic example of coordinated cell death. Weaning results in the distension of the alveolar structures by the accumulation of milk, which, in turn, activates STAT3 and initiates a caspase-independent but lysosome-dependent cell death (LDCD) pathway. Although the importance of STAT3 and LDCD in early mammary involution is well established, it has not been entirely clear how milk stasis activates STAT3. In this report, we demonstrate that protein levels of the PMCA2 calcium pump are significantly downregulated within 2-4 hours of experimental milk stasis. Reductions in PMCA2 expression correlate with an increase in cytoplasmic calcium in vivo as measured by multiphoton intravital imaging of GcAMP6f fluorescence. These events occur concomitant with the appearance of nuclear pSTAT3 expression and prior to significant activation of LIF, IL6 and TGFb3 production or LDCD. Interestingly, we observed the activation of TFEB led by activation of TGFb signaling and deactivation of mTOR signaling in the involution of mammary gland. Finally, we demonstrate that increased intracellular calcium activates STAT3 by degrading SOCS3 mediated by TGFb signaling. In summary, these data suggest that intracellular calcium serves as an important biochemical signal linking milk stasis to STAT3 activation, increased lysosome biogenesis, and lysosome-mediated cell death.

2022-12-01 | GSE190031 | GEO

Expression data from an involution time course in wild type and E2F3 +/- mice.

Project description:We have compared an involution timecourse for wild type and E2F3 heterozygous mice on the Operon 3.0 platform. Three mice were taken for each genotype at each timepoint (Involution day 0, 1, 2, 3 and 4) and RNA was prepared from the mammary glands. The RNA from each mouse was pooled and run as an individual sample. Keywords: Mouse Mammary Gland RNA 5 timepoints, 2 genotypes, 3 replicates per timepoint.

2008-07-11 | E-GEOD-11066 | biostudies-arrayexpress

Expression data from an involution time course in wild type and E2F3 +/- mice.

2008-07-11 | GSE11066 | GEO

Involution day 2, mouse mammary gland Rac1 knockout mice.

Project description:The microarray was conducted from RNA isolated from mouse mammary glands harvested from Involution day 2 mice. Cre-mediated specific Rac1 gene deletion in luminal mammary epithelial cells was achieved by crossing Rac1fx/fxRosaYFP mice with WAPiCreTg/â¢ mice to produce Rac1fx/fxYFP ;WAPiCreTg/â¢ (Rac1-/-) mice. Rac1fx/fxYFP mice that lacked the Cre gene were used as wild type (WT) controls. The RNA was isolated from the inguinal gland 4 for each mouse

2016-10-31 | E-MTAB-5019 | biostudies-arrayexpress

Analysis of human breast milk cells: gene expression profiles during pregnancy, lactation, involution and mastitic infection.

Project description:The molecular processes underlying human milk production and the effects of mastitic infection are largely unknown because of limitations in obtaining tissue samples. Determination of gene expression in normal lactating women would be a significant step towards understanding why some women display poor lactation outcomes. Here we demonstrate the utility of RNA obtained directly from human milk cells to detect mammary epithelial cell (MEC)-specific gene expression. Milk cell RNA was collected from 5 time points (24 hours pre-partum during the colostrum period, mid lactation, two involution, and during a bout of mastitis) in addition to an involution series comprising three time points. Gene expression profiles were determined by use of human Affymetrix arrays. Milk cells collected during milk production showed that the most highly expressed genes were involved in milk synthesis (eg. CEL, OLAH, FOLR1, BTN1A1, ARG2), while milk cells collected during involution showed a significant down regulation of milk synthesis genes and activation of involution associated genes (eg. STAT3, NF-kB, IRF5, IRF7). Milk cells collected during mastitic infection revealed regulation of a unique set of genes specific to this disease state, whilst maintaining regulation of milk synthesis genes. Use of conventional epithelial cell markers was used to determine the population of MECâ??s within each sample. This paper is the first to describe the milk cell transcriptome across the human lactation cycle and during mastitic infection, providing valuable insight into gene expression of the human mammary gland. Human milk sampling throughout lactation cycle and during mastitic infection.

2016-04-01 | E-GEOD-77978 | biostudies-arrayexpress

Genome-wide transcriptional effects of Pregnancy-Induced Non-coding RNA (PINC)

Project description:Pregnancy-Induced Non-Coding RNA (PINC) is upregulated in alveolar cells of the mammary gland during pregnancy and persist in alveolar cells that remain in the regressed lobules following involution. Here, we show that in the post-pubertal mouse mammary gland, mPINC expression increases throughout pregnancy and then declines in early lactation, when alveolar cells undergo terminal differentiation. Accordingly, mPINC expression is significantly decreased when HC11 mammary epithelial cells are induced to differentiate and produce milk proteins. This natural reduction in mPINC levels may be necessary for lactation, as overexpression of mPINC in HC11 cells blocks lactogenic differentiation, while knockdown of mPINC enhances differentiation. HC11 mammary epithelial cells, with or without knockdown or over-expression of PINC, and with or without treatment by differentiation-inducing agents, were profiled for gene expression.

2012-08-08 | E-GEOD-38052 | biostudies-arrayexpress

Genome-wide transcriptional effects of Pregnancy-Induced Non-coding RNA (PINC)

2012-08-09 | GSE38052 | GEO

Analysis of human breast milk cells: gene expression profiles during pregnancy, lactation, involution and mastitic infection.

Project description:The molecular processes underlying human milk production and the effects of mastitic infection are largely unknown because of limitations in obtaining tissue samples. Determination of gene expression in normal lactating women would be a significant step towards understanding why some women display poor lactation outcomes. Here we demonstrate the utility of RNA obtained directly from human milk cells to detect mammary epithelial cell (MEC)-specific gene expression. Milk cell RNA was collected from 5 time points (24 hours pre-partum during the colostrum period, mid lactation, two involution, and during a bout of mastitis) in addition to an involution series comprising three time points. Gene expression profiles were determined by use of human Affymetrix arrays. Milk cells collected during milk production showed that the most highly expressed genes were involved in milk synthesis (eg. CEL, OLAH, FOLR1, BTN1A1, ARG2), while milk cells collected during involution showed a significant down regulation of milk synthesis genes and activation of involution associated genes (eg. STAT3, NF-kB, IRF5, IRF7). Milk cells collected during mastitic infection revealed regulation of a unique set of genes specific to this disease state, whilst maintaining regulation of milk synthesis genes. Use of conventional epithelial cell markers was used to determine the population of MEC’s within each sample. This paper is the first to describe the milk cell transcriptome across the human lactation cycle and during mastitic infection, providing valuable insight into gene expression of the human mammary gland.

2016-04-01 | GSE77978 | GEO

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