Breast cancer and liver tissue biopsies used to develop and validate an index for liver contamination in metastatic breast cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE33116 | GEO | 2013/01/05
SECONDARY ACCESSION(S): PRJNA149361
REPOSITORIES: GEO
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Project description:PURPOSE: To develop an index capable of detecting and quantifying the extent of liver RNA contamination in liver biopsies of metastatic breast cancer METHODS: We developed a microarray-based gene expression liver index by comparing the expression levels of genes in liver tissue biopsies and in primary breast cancer biopsies. The predictive performance of the index was then evaluated in defined mixtures of liver and breast cancer RNA. A calibration curve was established to allow estimation of the liver RNA content in unknown metastatic breast cancer samples. A set of liver biopsies and primary breast cancer biopsies were used to identify genes that were expressed significantly higher in liver tissue. These genes were used in a liver index, which was validated in a new set of liver and primary breast cancer biopsies. A set of liver/breast cancer RNA mixtures was used to establish a calibration curve to allow quantification of liver contamination in metastatic breast cancer samples. The prediction error of the calibration curve was assessed in a new set of liver/breast cancer RNA mixtures and applied to estimate the liver content in a set of unknown metastatic breast cancer biopsies.
2013-01-05 | E-GEOD-33116 | biostudies-arrayexpress
Project description:Breast cancer and liver tissue biopsies used to develop and validate an index for liver contamination in metastatic breast cancer
| PRJNA149361 | ENA
Project description:Metabolic rewiring is essential for breast tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. Transcriptional and metabolomic analysis have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic profile characterized by increased HIF-1α activity and dependence on glycolysis. Stable isotope tracing analysis (SITA) performed in vivo confirmed that the glycolytic nature of liver-metastatic breast cancer cells is retained when these cells are grown as primary tumors or as liver metastases. However, our data also reveal that unique metabolic adaptations are specifically induced by the liver microenvironment. Indeed, liver metastases display elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to primary tumors. Moreover, breast cancer liver metastases rely strongly on glucose and glutamine-derived carbons to support de novo GSH synthesis. Glutathione is a tripeptide that acts as a major scavenger for reactive oxygen species (ROS). Liver metastases display reduced levels of 8-Oxo-2'-deoxyguanosine, confirming their increased capacity to buffer ROS. We demonstrated the dependence of liver metastases formation on these distinct metabolic adaptations by depleting glutamate-cysteine ligase (Gcl), the rate-limiting enzyme in glutathione biosynthesis. Gcl depletion, and decreased GSH levels, strongly reduced the capacity of liver-metastatic cells to form distant metastasis within the liver. We performed gene expression analysis of liver metastasis and primary tumors from liver-metastatic breast cancer cells derived from 4T1 cells. 4T1-2776 (76) and 4T1-2792 (92) cells were injected in the mammary fat pads of BALB/c and grown as primary tumors or were grown as liver metastasis after splenic injection. Tissues were harvested from primary tumors and liver metastasis and submitted to laser-capture microdissection (LCM). For liver metastasis, tumour tissue was harvested at 10 days, 2 weeks and 3 weeks after splenic injection. For each time point, tissue was isolated from the tumor centre (core), a peripheral area of the tumor (margin), a region of the liver proximal to the tumor (adjacent) and a region of the liver far from the tumor (distant). For primary tumors from 4T1-2776 cells (1034, 1036, 1043) and 4T1-2792 (MFP2L, MFP3L, MFP5L) tissue was collected from the tumor core and margin, at the experimental endpoint.
2023-07-25 | GSE238214 | GEO
Project description:Breast cancer cells display preferences for specific metastatic sites including the bone, lung and liver. Metastasis is a complex process that relies, in part, on interactions between disseminated cancer cells and resident/infiltrating stromal cells that constitute the metastatic microenvironment. Distinct immune infiltrates can either impair the metastatic process or conversely, assist in the seeding, colonization and growth of disseminated cancer cells. Using in vivo selection approaches, we previously isolated 4T1-derived breast cancer cells that preferentially metastasize to these organs and tissues. In this study, we examined whether the propensity of breast cancer cells to metastasize to the lung, liver or bone is associated with and dependent on distinct patterns of immune cell infiltration. Immunohistocytochemistry and immunohistofluorescence approaches were used to quantify granulocytic infiltrates within distinct metastases and depletion of Gr1+ cells was performed to functionally interrogate the role of myeloid/granulocytic infiltrates in promoting metastasis to these organs. We show that T lymphocytes (CD3+), myeloid-derived/granulocytic cells (Gr-1+) cells and neutrophils (NE+) exhibit the most pronounced recruitment in lung and liver metastases, with markedly less recruitment within bone metastatic lesions. Interestingly, these infiltrating cell populations display different patterns of localization within soft tissue metastases. T lymphocytes and neutrophils are localized around the periphery of liver metastases whereas they were dispersed throughout the lung metastases. Furthermore, Gr-1+ cell-depletion studies demonstrate that infiltrating myeloid-derived/granulocytic cells, including neutrophils, are essential for the formation of breast cancer liver metastases but dispensable for metastasis to the lung and bone. Finally, we demonstrate that neutrophils that infiltrate and surround the liver metastases are polarized towards an N2 phenotype, which have previously been shown to enhance tumor growth and metastasis. Our results demonstrate that the liver metastatic potential of breast cancer cells is heavily reliant on interactions with infiltrating myeloid/granulocytic cells in the liver microenvironment.
2015-03-20 | GSE62598 | GEO
Project description:There is clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SET ER/PR index to measure gene expression microarray probe sets that were correlated with hormone receptors (ESR1 and PGR) and robust to pre-analytical and analytical influences. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SETER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955, p = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SETER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SET ER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.485, 95% CI 0.265 to 0.889, p = 0.019; OS: HR 0.314, 95% CI 0.155 to 0.637, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SET ER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript.
2019-05-30 | GSE124647 | GEO
Project description:Metastasis accounts for 90% of cancer-related deaths, yet the mechanisms by which cancer cells colonize secondary organs remain poorly understood. For breast cancer patients, metastasis to the liver is associated with poor prognosis and a median survival of 6 months. Standard of care is chemotherapy, but recurrence occurs in 30% of patients. Systemic chemotherapy has been shown to induce hepatotoxicity and fibrosis, but how chemotherapy impacts the composition of the liver extracellular matrix (ECM) remains unknown. Individual ECM proteins drive tumor cell proliferation and invasion, features that are essential for metastatic outgrowth in the liver. Here, we characterize the liver ECM of tumor-bearing mice treated with and without chemotherapy using the MMTV-PyMT transgenic model of breast cancer. We identify distinct drug-specific changes induced by commonly used cytotoxic chemotherapies. We identify Collagen V as an ECM protein that is more abundant in livers isolated from paclitaxel-treated mice and identify mechanisms of Collagen V driven invasion via ECM organization and signaling through α1β1 integrins.
2022-10-05 | PXD036736 | Pride
Project description:There is clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SETER/PR index to measure gene expression microarray probe sets that were correlated with hormone receptors (ESR1 and PGR) and robust to pre-analytical and analytical influences. We tested SETER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SETER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SETER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955, p = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SETER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SETER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript.
2019-05-30 | GSE124648 | GEO
Project description:To develop a classifier based on microRNAs for primary tumor site identification of liver core biopsies and to explore the influence of surrounding normal liver tissue on classification. Tissue samples from 333 patients, corresponding to one of the following ten assay classes, were obtained from archives of the pathology department, Copenhagen University Hospital, Rigshospitalet, Denmark: Lung cancer, breast cancer, gastric/cardia cancer, colorectal cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, cholangiocarcinoma, squamous cell cancers of different origin, and normal liver tissue
2013-10-19 | E-GEOD-51429 | biostudies-arrayexpress
Project description:Estrogen receptor–positive (ERþ) metastatic tumors contribute to nearly 70% of breast cancer–related deaths. Most patients with ERþ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor antagonist fulvestrant as standard of care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared with other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER targeting agents remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ERþ liver metastases. We therefore evaluated site specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ERþ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ERþ tumor metastatic sites (liver, lung, and bone), and in vivo, in liver and lung metastasis mouse models. ERþ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregu lated expression of glucose metabolism enzymes in response to fulvestrant. Furthermore, differential ERa activity, but not expres sion, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of fulves trant treatment to reduce the metastatic burden. Our findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment.
2023-07-13 | GSE236681 | GEO
Project description:Estrogen receptor-positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer-related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor agonist fulvestrant (Fulv) as standard of care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared to other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER agonists remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ER+ tumor metastatic sites (liver, bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to Fulv. Furthermore, differential ERαERα activity, but not expression, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of Fulv treatment to reduce the metastatic burden. Our findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment. These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases.
2022-06-15 | GSE184156 | GEO