Transition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mechanism
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PROVIDER: PRJNA378531 | ENA |
REPOSITORIES: ENA
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Project description:The role of adipocytes in cancer microenvironment has gained focus during the recent years. However, the characteristics of the cancer-associated adipocytes (CAA) in human breast cancer tissues and the underlying regulatory mechanism are not clearly understood. We reviewed pathology specimens of breast cancer patients to understand the morphologic characteristics of CAA, and profiled the mRNA and miRNA expression of CAA by using indirect co-culture system in vitro. The CAAs in human breast cancers showed heterogeneous topographic relationship with breast cancer cells within the breast microenvironment. The CAAs exhibited the characteristics of de-differentiation determined by their microscopic appearance and the expression levels of adipogenic markers. Additionally, the 3T3-L1 adipocytes indirectly co-cultured with breast cancer cells showed up-regulation of inflammation-related genes including Il6 and Ptx3. The up-regulation of IL6 in CAA was further observed in human breast cancer tissues. miRNA array of indirectly co-cultured 3T3-L1 cells showed increased expression of mmu-miR-5112 which may target Cpeb1. Cpeb1 is a negative regulator of Il6. The suppressive role of mmu-miR-5112 was confirmed by dual luciferase reporter assay, and mmu-miR-5112-treated adipocytes showed up-regulation of Il6. The transition of adipocytes into more inflammatory CAA resulted in proliferation-promoting effect in ER positive breast cancer cells such as MCF7 and ZR-75-1 but not in ER negative cells. In this study, we have determined the de-differentiated and inflammatory natures of CAA in breast cancer microenvironment. Additionally, we propose a miRNA-based regulatory mechanism underlying the process of acquiring inflammatory phenotypes in CAA.
| S-EPMC5363867 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-03-09 | GSE95829 | GEO
Project description:The role of adipocytes in cancer microenvironment has gained focus during the recent years. However, the characteristics of the cancer-associated adipocytes (CAA) in human breast cancer tissues and the underlying regulatory mechanism are not clearly understood. We reviewed pathology specimens of breast cancer patients to understand the morphologic characteristics of CAA, and profiled the mRNA and miRNA expression of CAA by using indirect co-culture system in vitro.
2017-03-09 | GSE95828 | GEO
Project description:The role of adipocytes in cancer microenvironment has gained focus during the recent years. However, the characteristics of the cancer-associated adipocytes (CAA) in human breast cancer tissues and the underlying regulatory mechanism are not clearly understood. We reviewed pathology specimens of breast cancer patients to understand the morphologic characteristics of CAA, and profiled the mRNA and miRNA expression of CAA by using indirect co-culture system in vitro.
2017-03-09 | GSE95827 | GEO
Project description:Cancer development and progression depend on tumor cell intrinsic factors, the tumor microenvironment and host characteristics. Despite the identification of the plasticity of adipocytes, the primary breast stromal cells, both in physiology and cancer, we lack a complete understanding of mechanisms that regulate adipocyte-tumor cell crosstalk. Here we dissected the breast cancer crosstalk with adipocytes and studied relevant molecules. We identified that the ability of breast cancer cells to dedifferentiate adipocytes is intrinsic subtype-dependent, with all breast cancer subtypes, except for HER2+ER+ subtype, capable of inducing this phenomenon. Crosstalk between breast cancer cells and adipocytes in vitro increased cancer stem-like features and recruitment of pro-tumorigenic immune cells, through chemokine production. Serum amyloid A1 (SAA1) was in vitro identified as a regulator of the adipocyte dedifferentiation program in triple-negative breast cancer (TNBC) through CD36 and P2XR7 signaling. In human TNBCs, SAA1 expression was associated with CAA infiltration, inflammation, stimulated lipolysis, stem-like properties and distinct tumor immune microenvironment. Our findings provide evidence that interaction between tumor cells and adipocytes through SAA1 release is relevant to the aggressiveness of TNBC, potentially supporting its targeting.
2024-01-15 | PXD041186 | Pride
Project description:The tumor microenvironment, including adipocytes, is a critical element for breast cancer (BC) progression, also responding to metabolic stimuli characterizing obesity and/or diabetes. The reciprocal reprogramming established between BC cells and adipocytes remains to be deciphered. We investigated (i) the effect of mammary adipocytes on BC cells and vice versa, (ii) the impact of glucose on BC cells, adipocytes and (iii) the impact of glucose on their cross-talk. We have identified adipocyte-modulated genes in BC cells and BC cell-modulated genes in adipocytes, dependently and independently of glucose levels. We identified the adipogenesis process as the most relevantly differentially regulated pathway both in cancer cells and in adipocytes upon exposure to high glucose concentration. Specifically, we observed that BC cells promote de-differentiation of adipocytes and re-shaping toward a fibroblast-like phenotype, particularly upon glucose lowering; the de-lipidation of adipocytes is paralleled by induction of adipogenesis genes in BC cells.
2024-09-19 | GSE243555 | GEO
Project description:The purpose of this study is to identify miRNA expression changes in adipocyte-associated breast cancer microenvironment by using indirect in vitro co-culture system. We performed small RNA small RNA deep sequencing in human breast cancer cells and breast cancer cells co-cultured with mature adipocytes. We identified 98 differentially expressed miRNAs in breast cancer cells co-cultured with adipocytes using small RNA deep sequencing.
2019-08-20 | GSE118342 | GEO
Project description:The progression of noninvasive ductal carcinoma in situ to invasive ductal carcinoma for patients with breast cancer results in a significantly poorer prognosis and is the precursor to metastatic disease. In this work, we have identified insulin-like growth factor–binding protein 2 (IGFBP2) as a potent adipocrine factor secreted by healthy breast adipocytes that acts as a barrier against invasive progression. In line with this role, adipocytes differentiated from patient-derived stromal cells were found to secrete IGFBP2, which significantly inhibited breast cancer invasion. This occurred through binding and sequestration of cancer-derived IGF-II. Moreover, depletion of IGF-II in invading cancer cells using small interfering RNAs or an IGF-II–neutralizing antibody ablated breast cancer invasion, highlighting the importance of IGF-II autocrine signaling for breast cancer invasive progression. Given the abundance of adipocytes in the healthy breast, this work exposes the important role they play in suppressing cancer progression and may help expound upon the link between increased mammary density and poorer prognosis.
2023-07-13 | PXD036479 | Pride
Project description:The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and of breast tumors, undergo transcriptional, metabolic and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an immunosuppressive tumor microenvironment, including increased abundance of myeloid-derived suppressor cells and elevated expression of the checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of several common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 loss in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 may act as a tumor suppressor. Further elucidation of the interplay between p53 mutations and adipocytes within the tumor microenvironment may suggest novel therapeutic targets for the treatment of breast cancer patients.
2024-07-01 | GSE238231 | GEO
Project description:The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and of breast tumors, undergo transcriptional, metabolic and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an immunosuppressive tumor microenvironment, including increased abundance of myeloid-derived suppressor cells and elevated expression of the checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of several common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 loss in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 may act as a tumor suppressor. Further elucidation of the interplay between p53 mutations and adipocytes within the tumor microenvironment may suggest novel therapeutic targets for the treatment of breast cancer patients.
2024-07-01 | GSE238230 | GEO