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Induction of Senescence During Postpartum Mammary Gland Involution supports tissue remodeling and promotes postpartum tumorigenesis

ABSTRACT: Cellular senescence is an evolutionarily conserved stress response which contributes to tissue repair and tumor suppression, yet its accumulation is also linked to aging and disease. Whether physiological senescence can be exploited by oncogenic events to promote tumorigenesis is unknown. Postpartum mammary gland involution is a major adult tissue-remodeling event, resembling wound healing, and is closely associated with postpartum breast cancer (PPBC). Here, we show that during mammary gland involution in mice, a p16-dependent senescence response is induced in alveolar luminal cells. Eliminating senescent cells disrupts tissue remodeling and delays involution, demonstrating their physiological importance. However, in a PPBC model where oncogenic activation coincides with involution, removing involution-associated senescent cells extended tumor latency. Mechanistically, senescent cells enhance tumor cell plasticity via the senescence-associated secretory phenotype (SASP), fostering metastasis. Our findings reveal that senescence, while required for postpartum tissue remodelling, can be hijacked to facilitate tumorigenesis, defining senescence as a unifying mechanism linking tissue repair to tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE285005 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description:Mammary gland involution represents one of the most dramatic examples of programmed cell death/apoptosis and tissue regression during development, yet large gaps still exist in the understanding of the mechanisms involved, and the key factors that trigger involution, are not yet identified. With the focus on identifying “novel” genes associated with mammary gland regression, we used microarray analysis to examine differentially expressed genes during early mammary gland involution in the mouse. We believe that such analysis may facilitate the identification of genes that report on proliferative changes in the breast, particularly with regards to growth arrest and growth inhibition. We further reasoned that genes that inhibit mammary gland proliferation might have relevance to breast tumorigenesis since cancer is generally associated with a defect in apoptosis and cell growth arrest. Gene expression from day 0 (D0) of involution was compared to day 1 (D1, 24 hr post weaning) to identify genes exhibiting differential expression. A total of 5,826 genes were identified as being differentially expressed. Changes in gene expression were confirmed by quantitative real time PCR analysis of 21 randomly selected genes. Following the selection of a number of highly regulated mouse genes within this cohort, database searches were then employed to identify genes associated with human tumorigenesis. With an ultimate goal being the identification of genes, which under normal physiological conditions, inhibit breast proliferation, and therefore have the potential to impact on the clinical management of breast cancer, we further examined their relevance to human tumorigenesis. Among genes identified as having human homologues, and with previously established links to human tumorigenesis, were several known genes among the top 200 differentially expressed genes including EGF, EGFR, TGFß2, PTHLH, IGFBP1, that were down regulated. Upregulated known genes included ANNEXIN A1 and A3, THYMOSIN BETA 10, IGFBP5, LIF, BID, BCL2, JUN, KIT, and CLAUDIN 1. CLAUDIN 1 was the most highly upregulated gene in our dataset. Moreover, we identified a number of genes not previously implicated or not well characterized in human breast cancer including ANGPTL4, SLC34A2, GOS2, STEAP, SOX4, TNFRSF12A and SAA2. The expression levels of these genes in human breast cancer were confirmed in breast cancer cell lines and breast tumor tissues. For some of these genes, expression was consistently down regulated in a small panel of human breast tumor specimens. We believe that these genes now warrant further investigation to determine their relevance to human breast tumorigenesis and their potential utility as therapeutic targets for human breast cancer. This pilot study was used to demonstrate proof of principle that through the analysis of gene expression during mammary gland involution, it may be indeed possible to identify “novel” genes relevant to the growth arrest in the mammary gland and relevant to human breast cancer. Keywords: comparative expression analysis of involuting mouse mammary gland

Project description:Mammary gland involution represents one of the most dramatic examples of programmed cell death/apoptosis and tissue regression during development, yet large gaps still exist in the understanding of the mechanisms involved, and the key factors that trigger involution, are not yet identified. With the focus on identifying ânovelâ genes associated with mammary gland regression, we used microarray analysis to examine differentially expressed genes during early mammary gland involution in the mouse. We believe that such analysis may facilitate the identification of genes that report on proliferative changes in the breast, particularly with regards to growth arrest and growth inhibition. We further reasoned that genes that inhibit mammary gland proliferation might have relevance to breast tumorigenesis since cancer is generally associated with a defect in apoptosis and cell growth arrest. Gene expression from day 0 (D0) of involution was compared to day 1 (D1, 24 hr post weaning) to identify genes exhibiting differential expression. A total of 5,826 genes were identified as being differentially expressed. Changes in gene expression were confirmed by quantitative real time PCR analysis of 21 randomly selected genes. Following the selection of a number of highly regulated mouse genes within this cohort, database searches were then employed to identify genes associated with human tumorigenesis. With an ultimate goal being the identification of genes, which under normal physiological conditions, inhibit breast proliferation, and therefore have the potential to impact on the clinical management of breast cancer, we further examined their relevance to human tumorigenesis. Among genes identified as having human homologues, and with previously established links to human tumorigenesis, were several known genes among the top 200 differentially expressed genes including EGF, EGFR, TGFÃ2, PTHLH, IGFBP1, that were down regulated. Upregulated known genes included ANNEXIN A1 and A3, THYMOSIN BETA 10, IGFBP5, LIF, BID, BCL2, JUN, KIT, and CLAUDIN 1. CLAUDIN 1 was the most highly upregulated gene in our dataset. Moreover, we identified a number of genes not previously implicated or not well characterized in human breast cancer including ANGPTL4, SLC34A2, GOS2, STEAP, SOX4, TNFRSF12A and SAA2. The expression levels of these genes in human breast cancer were confirmed in breast cancer cell lines and breast tumor tissues. For some of these genes, expression was consistently down regulated in a small panel of human breast tumor specimens. We believe that these genes now warrant further investigation to determine their relevance to human breast tumorigenesis and their potential utility as therapeutic targets for human breast cancer. This pilot study was used to demonstrate proof of principle that through the analysis of gene expression during mammary gland involution, it may be indeed possible to identify ânovelâ genes relevant to the growth arrest in the mammary gland and relevant to human breast cancer. Experiment Overall Design: Pooled RNA from D0 mice and from D1 mice, (five mice per time point), was compared for differential gene expression by microarray analysis conducted by Paradigm Array Labs (Research Triangle Park, North Carolina, USA). The Affymetrix GeneChip Mouse Genome 430 Plus 2.0 Array (Affymetrix, Santa Clara CA. USA) was used. The array contained 45,100 probe sets (The Affymetrix probe-set identificator) and represented 39,000 transcripts. The Affymetrix Statistical Algorithms, implemented in the Affymetrix Microarray Suite 5.0 software, were used in the expression analysis of GeneChip probe arrays.

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Induction of Senescence During Postpartum Mammary Gland Involution supports tissue remodeling and promotes postpartum tumorigenesis

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