Effects of tumor stroma interaction on global gene expression in breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10006-10006
Author(s):  
M. Buess ◽  
D. Nuyten ◽  
T. Hastie ◽  
P. O. Brown
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Cells ◽  
Ex Vivo ◽  
Early Stage ◽  
Tumor Stroma ◽  
Cell Interaction ◽  
Interferon Response ◽  
Breast Cancer Cell Lines ◽  
Cell Cell

10006 Background: Perturbations in cell-cell interaction are a key feature of cancer. However, the systematic effects of cell-cell interaction on global gene expression in cancer are largely unexplored. We hypothesized that gene expression signatures induced by cell-cell interaction might be of clinical relevance. Methods: We simulated tumor-stroma interaction in vitro by systematically co-cultivating each of 7 different breast cancer cell lines with stromal fibroblasts from 3 different sites, and determined associated gene expression changes with cDNA microarrays. A dataset of pretreatment gene expression profiles from 295 early stage breast cancers (stage 1 and 2) with a median follow up of 12.6 years allowed us to evaluate the prognostic significance of the gene expression signatures of specific cell-cell interactions derived from our ex vivo models. Results: The most prominent response to epithelial-mesenchymal interaction was an induction of interferon-response genes (IRG), observed in 4 of the 7 breast cancer cell lines in co-culture with fibroblasts, but not in normal mammary epithelial cells. In response to close contact with these breast cancer cells, the fibroblasts secreted type I interferons, which, in turn, induced expression of the IRG in the tumor cells. Immunohistochemical analysis of human breast cancer tissues showed that Stat1, the key transcriptional activator of the IRG, and itself an IRG, was expressed in a subset of the cancers, with a striking pattern of elevated expression in the cancer cells in contact with, or close proximity to, the tumor stroma - paralleling the response seen in our ex vivo model. In vivo, expression of the IRGs was remarkably coherent, providing a basis for segregation of the 295 early-stage breast cancers into two groups by unsupervised hierarchical clustering with the IRG. Tumors with high expression levels (n=161) of IRG were associated with significantly shorter overall survival; 59% at 10 years versus 80% at 10 years for tumors with low expression levels (n=134) (log-rank p=0.001). Conclusions: Our results suggest that an interaction between some breast cancer cells and stromal fibroblasts can induce an interferon response, and that this response may be associated with a greater propensity for tumor progression. No significant financial relationships to disclose.

scholarly journals Periostin gene expression in neu-positive breast cancer cells is regulated by a FGFR signaling cross talk with TGFβ/PI3K/AKT pathways

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Cédrik Labrèche ◽  
David P. Cook ◽  
John Abou-Hamad ◽  
Julia Pascoal ◽  
Benjamin R. Pryce ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Breast Cancer Cell Lines ◽  
Matricellular Protein ◽  
Stromal Compartment ◽  
Primary Tumors

Abstract Background Breast cancer is a highly heterogeneous disease with multiple drivers and complex regulatory networks. Periostin (Postn) is a matricellular protein involved in a plethora of cancer types and other diseases. Postn has been shown to be involved in various processes of tumor development, such as angiogenesis, invasion, cell survival and metastasis. The expression of Postn in breast cancer cells has been correlated with a more aggressive phenotype. Despite extensive research, it remains unclear how epithelial cancer cells regulate Postn expression. Methods Using murine tumor models and human TMAs, we have assessed the proportion of tumor samples that have acquired Postn expression in tumor cells. Using biochemical approaches and tumor cell lines derived from Neu+ murine primary tumors, we have identified major regulators of Postn gene expression in breast cancer cell lines. Results Here, we show that, while the stromal compartment typically always expresses Postn, about 50% of breast tumors acquire Postn expression in the epithelial tumor cells. Furthermore, using an in vitro model, we show a cross-regulation between FGFR, TGFβ and PI3K/AKT pathways to regulate Postn expression. In HER2-positive murine breast cancer cells, we found that basic FGF can repress Postn expression through a PKC-dependent pathway, while TGFβ can induce Postn expression in a SMAD-independent manner. Postn induction following the removal of the FGF-suppressive signal is dependent on PI3K/AKT signaling. Conclusion Overall, these results reveal a novel regulatory mechanism and shed light on how breast tumor cells acquire Postn expression. This complex regulation is likely to be cell type and cancer specific as well as have important therapeutic implications.

scholarly journals Lipid Profile and Aquaporin Expression under Oxidative Stress in Breast Cancer Cells of Different Malignancies

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Claudia Rodrigues ◽  
Lidija Milkovic ◽  
Ivana Tartaro Bujak ◽  
Marko Tomljanovic ◽  
Graça Soveral ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Lipid Profile ◽  
Cancer Cells ◽  
Triple Negative ◽  
Cell Types ◽  
Metabolic Reprogramming ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Oxidative Challenge

Breast cancer is the major cause of tumor-associated mortality in women worldwide, with prognosis depending on the early discovery of the disease and on the type of breast cancer diagnosed. Among many factors, lipids could contribute to breast cancer malignancy by participating in cellular processes. Also, aquaporins are membrane channels found aberrantly expressed in cancer tissues that were correlated with tumor aggressiveness, progression, and metastasis. However, the differences in lipid profile and aquaporin expression between cell types of different malignant potential have never been investigated. Here, we selected three breast cancer cell lines representing the three major breast cancer types (hormone positive, HER2NEU positive, and triple negative) and analyzed their lipid profile and steady state lipid hydroperoxide levels to correlate with cell sensitivity to H2O2. Additionally, the expression profiles of AQP1, AQP3, and AQP5 and the Nrf2 transcription factor were evaluated, before and after oxidative challenge. We found that the lipid profile was dependent on the cell type, with the HER2-positive cells having the lowest level PUFA, whereas the triple negative showed the highest. However, in triple-negative cancer cells, a lower level of the Nrf2 may be responsible for a higher sensitivity to H2O2 challenge. Interestingly, HER2-positive cells showed the highest increase in intracellular ROS after oxidative challenge, concomitant with a significantly higher level of AQP1, AQP3, and AQP5 expression compared to the other cell types, with AQP3 always being the most expressed isoform. The AQP3 gene expression was stimulated by H2O2 treatment in hormone-positive and HER2NEU cells, together with Nrf2 expression, but was downregulated in triple-negative cells that showed instead upregulation of AQP1 and AQP5. The lipid profile and AQP gene expression after oxidative challenge of these particularly aggressive cell types may represent metabolic reprogramming of cancer cells and reflect a role in adaptation to stress and therapy resistance.

scholarly journals MMP1 and MMP11 expression in Peripheral Blood Mononuclear Cells upon their interaction with Breast Cancer Cells and Fibroblasts

2020 ◽  
Author(s):  
Noemi Eiro ◽  
Sandra Cid ◽  
Nuria Aguado ◽  
María Fraile ◽  
Jorge Rubén Cabrera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Inflammatory Genes

Abstract Background: Tumor-infiltrating immune cells phenotype is associated with tumor progression. However, little is known about the phenotype of the Peripheral Blood Mononuclear Cells (PBMC) from breast cancer patients. Here, we investigated the expression of MMP1 and MMP11 in PBMC from breast cancer patients and we analyzed gene expression changes upon their interaction with cancer cells and Cancer-Associated Fibroblasts (CAF). Finally, we measured the impact of PBMC in proinflammatory genes expression in normal fibroblast and CAF.Results: Gene expression of MMP1 and MMP11 in PBMC from breast cancer patients (n=54) and control (n=28), and expression of IL1A, IL6, IL17, IFNβ and NFB in breast cancer cell lines (MCF-7 and MDA-MB-231), CAF and in Normal Fibroblasts (NF) were analyzed by qRT-PCR before and after co-culture. Our results show the existence of a group of breast cancer patients (25.9%) with very high levels of MMP11 gene expression in PBMC. Also, we present evidence of increased gene expression of MMP1 and MMP11 in PBMC after co-culture with breast cancer cell lines, NF or CAF. Finally, we show a differential expression profile of inflammatory genes in NF and CAF when co-cultured with control or breast cancer PBMC.Conclusions: We have observed that MMPs expression in PBMC is regulated by the microenvironment, while the expression of inflammatory genes in NF or CAF is differentially regulated by control or breast cancer PBMC. These findings confirm the importance of the interaction and communication between stromal cells and suggest that PBMC would play a role to promote an aggressive tumor behavior.

scholarly journals Aberrant promoter methylation may be responsible for the control of CD146 (MCAM) gene expression during breast cancer progression

2019 ◽  
Author(s):  
Paulina Dudzik ◽  
Sonia Elzbieta Trojan ◽  
Barbara Ostrowska ◽  
Małgorzata Lasota ◽  
Joanna Dulińska-Litewka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Gene Promoter ◽  
Breast Cancer Cell Lines ◽  
Cd146 Expression

The CD146 (also known as MCAM, MUC-18, Mel-CAM) was initially reported in 1987, as a protein crucial for the invasiveness of malignant melanoma. Recently, it has been confirmed that CD146 has been involved in progression and poor overall survival of many cancers including breast cancer. Importantly, in independent studies, CD146 was reported to be a trigger of epithelial to mesenchymal transition in breast cancer cells. The goal of our current study was to verify the potential involvement of epigenetic mechanism behind the regulation of CD146 expression in breast cancer cells, as it has been previously reported in prostate cancer. First, we analysed the response of breast cancer cell lines, differing in the initial CD146 mRNA and protein content, to epigenetic modifier, 5-aza-2-deoxycytidine, and subsequently the methylation status of CD146 gene promoter was investigated, using direct bisulfite sequencing. We observed that treatment with demethylating agent led to induction of CD146 expression in all analysed breast cancer cell lines, both at mRNA and protein level, what was accompanied by increased expression of selected mesenchymal markers. Importantly, CD146 gene promoter analysis showed aberrant CpG island methylation in 2 out of 3 studied breast cancer cells lines, indicating epigenetic regulation of CD146 gene expression. In conclusion, our study revealed, for the first time, that aberrant methylation maybe involved in expression control of CD146, a very potent EMT inducer in breast cancer cells. Altogether, the data obtained may provide the basis for novel therapies as well as diagnostic approaches enabling sensitive and very accurate detection of breast cancer cells.

scholarly journals Patient-derived scaffolds as a drug-testing platform for endocrine therapies in breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Gustafsson ◽  
Elena Garre ◽  
Maria Carmen Leiva ◽  
Simona Salerno ◽  
Anders Ståhlberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Cells ◽  
Drug Testing ◽  
Expression Profiles ◽  
Surrounding Tissue ◽  
Breast Cancer Cell Lines ◽  
Mcf7 Cells ◽  
Testing Platform

AbstractThree-dimensional cell culture platforms based on decellularised patient-based microenvironments provide in vivo-like growth conditions allowing cancer cells to interact with intact structures and components of the surrounding tissue. A patient-derived scaffold (PDS) model was therefore evaluated as a testing platform for the endocrine therapies (Z)-4-Hydroxytamoxifen (4OHT) and fulvestrant as well as the CDK4/6-inhibitor palbociclib, monitoring the treatment responses in breast cancer cell lines MCF7 and T47D adapted to the patient-based microenvironments. MCF7 cells growing in PDSs showed increased resistance to 4OHT and fulvestrant treatment (100- and 20-fold) compared to 2D cultures. Quantitative PCR analyses of endocrine treated cancer cells in PDSs revealed upregulation of pluripotency markers further supported by increased self-renewal capacity in sphere formation assays. When comparing different 3D growth platforms including PDS, matrigel, gelatin sponges and 3D-printed hydrogels, 3D based cultures showed slightly varying responses to fulvestrant and palbociclib whereas PDS and matrigel cultures showed more similar gene expression profiles for 4OHT treatment compared to the other platforms. The results support that the PDS technique maximized to provide a multitude of smaller functional PDS replicates from each primary breast cancer, is an up-scalable patient-derived drug-testing platform available for gene expression profiling and downstream functional assays.

scholarly journals Profiling of histone H1 variants and changes on genome architecture and gene expression upon histone H1 depletion in breast cancer cells

2021 ◽  
Author(s):  
Núria Serna-Pujol ◽  
Mónica Salinas-Pena ◽  
Francesca Mugianesi ◽  
François Le Dily ◽  
Marc A. Marti-Renom ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Gc Content ◽  
Histone H1 ◽  
Interferon Response ◽  
Specific Gene ◽  
Genome Architecture ◽  
Gene Expression Response

AbstractHuman somatic cells may contain up to seven members of the histone H1 family contributing to chromatin compaction and its regulation. In breast cancer cells, knock-down (KD) of each H1 variant results in specific gene expression changes. We have previously shown that combined KD of H1.2 and H1.4 (H1 KD) deregulates many genes, promotes the appearance of accessibility sites genome wide and triggers an interferon response via activation of heterochromatic repeats. Here we describe for the first time ChIP-seq profiling of five endogenous H1 variants at the same time, obtaining that H1 variants are differentially distributed at low (H1.2, H1.5, H1.0) and high (H1X, H1.4) GC content regions. Further, we report that H1 KD promotes redistribution of some of the variants and changes on genome architecture. H1 KD decreased topologically associating domain (TAD) border strength as well as its interactions, both inter- and intra-TAD. In addition, many TADs presented a coordinated gene expression response to H1 KD. Up-regulated genes accumulate within TADs with low gene density and high H1.2 content. In conclusion, our data suggests that the equilibrium between distinct histone H1 variants helps maintaining the topological organization of the genome and the proper expression of particular gene programs.

scholarly journals MMP1 and MMP11 Expression in Peripheral Blood Mononuclear Cells upon Their Interaction with Breast Cancer Cells and Fibroblasts

2020 ◽  
Vol 22 (1) ◽  
pp. 371
Author(s):  
Noemi Eiro ◽  
Sandra Cid ◽  
Nuria Aguado ◽  
María Fraile ◽  
Nagore de Pablo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Breast Cancer Cells ◽  
Mononuclear Cells ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Peripheral Blood Mononuclear ◽  
The Impact

Tumor-infiltrating immune cells phenotype is associated with tumor progression. However, little is known about the phenotype of the peripheral blood mononuclear cells (PBMC) from breast cancer patients. We investigated MMP1 and MMP11 expression in PBMC from breast cancer patients and we analyzed gene expression changes upon their interaction with cancer cells and cancer-associated fibroblasts (CAF). We measured the impact of PBMC on proinflammatory gene expression in breast cancer cells, normal fibroblast (NF), and CAF and the impact on proliferation and invasiveness capacity of breast cancer cells. Gene expression of MMP1 and MMP11 in PBMC from breast cancer patients (n = 54) and control (n = 28); expression of IL1A, IL6, IL17, IFNβ, and NFĸB in breast cancer cell lines (MCF-7 and MDA-MB-231); and, additionally, IL10 and MMP11 in CAF and NF were analyzed by qRT-PCR before and after co-culture. Our results show the existence of a subpopulation of breast cancer patients (25.9%) with very high levels of MMP11 gene expression in PBMC. Also, gene expression of MMP1 and MMP11 increases in PBMC after co-culture with breast cancer cell lines, NF or CAF. PBMC from healthy or breast cancer patients induce an increased proliferation rate on MCF-7 and an increased invasiveness capacity of MDA-MB-231. Finally, we show a differential expression profile of inflammatory genes in NF and CAF when co-cultured with control or breast cancer PBMC. We have observed that MMPs’ expression in PBMC is regulated by the microenvironment, while the expression of inflammatory genes in NF or CAF is differentially regulated by PBMC. These findings confirm the importance of the crosstalk between stromal cells and suggest that PBMC would play a role in promoting aggressive tumor behavior.

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