Post-lactational involution promotes recruitment of local CD8+ T cells with a resident-phenotype that controls breast cancer growth
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ABSTRACT:
PROVIDER: PRJNA1130899 | ENA |
REPOSITORIES: ENA
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Project description:The mechanisms by which parity and breastfeeding mediate protection against breast cancer, particularly triple-negative breast cancer (TNBC), remain unclear. CD8+ T cells with a tissue-resident-like phenotype (TRM) are present in TNBCs and are associated with better clinical outcomes. In preclinical models of TNBC, CD8+ TRM-like cells can protect against BC recurrences. These cells are also present in healthy, non-cancer-affected breast tissue. We hypothesized that post-lactational involution could facilitate increased CD8+ T cell recruitment locally to the breast, improving immune surveillance against BC. Consistent with this, we observed significantly higher quantities of immune cells and CD103+CD8+ T cells in healthy breast tissue collected from parous vs. nulliparous women. In preclinical murine models, we observed that after a period of lactation and involution, CD8+ TRM-like cells increase in quantity the mammary gland. Using syngeneic models of TNBC, we show that these higher quantities of local CD8+ T cells in the mammary gland are associated with significantly decreased tumor growth, with higher intratumoral T cell content. We further find that parous women vs. nulliparous women who develop primary TNBC have significantly higher T cell infiltration in their tumors. Our data provide evidence that lactation and post-lactational involution result in quantitative and qualitative differences in local resident CD8+ T cells that can restrain mammary tumor outgrowth.
2025-09-12 | GSE271307 | GEO
Project description:The aim of this study is to assess the impact of cabergoline on the intensity of short-term post-lactational involution and to explore long-term alterations in the epithelial dynamics of the glandular component in Brca1/P53-deficient mice. This study also delves into the transcriptomic changes associated with these processes. To further investigate the molecular changes occurring at these temporal points, RNA sequencing (RNA-seq) was conducted 1 day after post-lactation involution and again at 60 days.
2024-01-10 | GSE250534 | GEO
Project description:Effect of Cabergoline on Post-Lactational Involution and Long-Term Mammary Gland Behavior.
| PRJNA1054495 | ENA
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
Project description:Adaptive immunity is didactically partitioned into humoral and cell-mediated effector mechanisms, which may imply that each arm is separate and does not function together. Here, we report that the activation of CD8+ resident memory T cells in nonlymphoid tissues triggers vascular permeability, which facilitates rapid distribution of serum antibodies into local tissues. TRM reactivation was associated with transcriptional upregulation of antiviral signaling pathways as well as Fc receptors and components of the complement cascade. Effects were local, but evidence is presented that TRM in brain and reproductive mucosa are both competent to induce rapid antibody exudation. TRM reactivation in the mouse female genital tract increased local concentrations of virus-specific neutralizing antibodies including anti-vesicular stomatitis virus and passively transferred anti-HIV antibodies. We showed that this response was sufficient to increase the efficacy of ex vivo vesicular stomatitis virus neutralization. These results indicate that CD8+ TRM antigen recognition can enhance local humoral immunity. Microarray data comparing RNA isolated from murine female reproductive tract tissue from control tissue (SIIN) versus tissues where resident memory T cells were reactivated 9 hours prior (GP33). Control mice (SIIN) received the irrelevant peptide SIINFEKL transcervically. Experimental mice (GP33) recieved the peptide gp33, which P14 resident memory T cells specifically recognize, transcervically.
2022-12-09 | GSE219002 | GEO
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.
2011-02-03 | GSE27012 | GEO
Project description:The goal was to study the long term metabolic programming effects of exposure of offspring to a dam eating 60% high fat diet during the lactation period only. We previously showed that offspring from dams given lactational high fat diet (HFD) are predisposed to obesity, glucose intolerance and inflammation. The purpose of these studies was to understand the programming implications of lactational HFD on offspring metabolic liver disease risk. Dams were fed a 60% lard-based HFD from the day of delivery through the 21 day lactation period. Starting at weaning offspring were fed normal fat diet until 3 months of age at which point a subset were challenged with an additional HFD stressor. Lactational HFD fed male offspring developed hepatic insulin resistance. Postweaning HFD challenge led male offspring progressing to NAFLD with more severe outcomes in the lactational HFD challenged offspring.
2021-08-14 | GSE182071 | GEO
Project description:This project tested the hypothesis that drying off and involution is accompanied by similar changes among the low abundance proteins as mastitis, thereby presenting a possible alternative means of maximising yields of host-defence-associated bioactive proteins.
2016-06-14 | PXD003110 | Pride
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
Project description:Macrophages are hematopoietic cells critical for innate immune defense, but also control organ homeostasis in a tissue-specific manner. Tissue-resident macrophages, therefore, provide a well-defined model to study the impact of ontogeny and microenvironment on chromatin state. Here, we profile the dynamics of four histone modifications across seven tissue-resident macrophage populations, as well as monocytes and neutrophils. We identify 12,743 macrophage-specific enhancers and establish that tissue-resident macrophages have distinct enhancer landscapes. Our work suggests that a combination of tissue and lineage-specific transcription factors form the regulatory networks controlling chromatin specification in tissue-resident macrophages. The environment has the capacity to alter the chromatin landscape of macrophages derived from transplanted adult bone marrow in vivo and even differentiated macrophages are reprogrammed when transferred into a new tissue. Altogether, these data provide a comprehensive view of macrophage regulation and highlight the importance of microenvironment along with pioneer factors in orchestrating macrophage identity and plasticity. 7 tissue-resident macrophage populations were isolated, as well as monocytes and neutrophils, and transcriptome analysis was performed. Experiment was done in duplicates.
2014-12-05 | E-GEOD-63340 | biostudies-arrayexpress