RET overexpression leads to increased brain metastatic competency in luminal breast cancer patients
Ontology highlight
ABSTRACT: Breast cancer brain metastasis is a rising occurrence, necessitating a better understanding of the mechanisms involved for effective management. Breast cancer brain metastases diverge significantly from the primary tumor, with gains in kinase and concomitant losses of steroid signaling observed. In this study, we explored the role of the kinase receptor RET in promoting breast cancer brain metastasis and provide a rationale for targeting the receptor in this patient cohort. Here, exome capture RNA sequencing data is deposited as sequencing batch corrected log2 transformed trimmed M of means (TMM) normalised counts per million (CPM) (log2(TMM-CPM +1) gene expression values for the patients described in this study (n=19,622 protein coding genes; N=16 tumour samples).
Project description:Brain metastatic disease occurs in 10-30% of metastatic breast cancer cases. The incidence of brain metastases is increasing with median overall survival < 2 years for patients. In order to better characterize oncogenic pathway activity pertinent to breast cancer brain metastasis, exome capture RNA sequencing was carried out on patient matched primary breast with brain metastatic tumor samples for 45 cases of breast cancer brain metastasis (N= 90 samples). Here, exome capture RNA sequencing data is deposited as sequencing batch corrected log2 transformed trimmed M of means (TMM) normalized counts per million (CPM) (log2(TMM-CPM +1) gene expression values (n=16,714 protein coding genes; N=90 tumor samples).
Project description:Brain metastatic disease occurs in 10-30% of metastatic breast cancer cases. The incidence of brain metastases is increasing with median overall survival < 2 years for patients. In order to better characterize oncogenic pathway activity pertinent to breast cancer brain metastasis, exome capture RNA sequencing was carried out on patient matched primary breast with brain metastatic tumor samples for 45 cases of breast cancer brain metastasis (N= 90 samples). Here, exome capture RNA sequencing data is deposited as sequencing batch corrected log2 transformed trimmed M of means (TMM) normalized counts per million (CPM) (log2(TMM-CPM +1) gene expression values (n=16,714 protein coding genes; N=90 tumor samples).
Project description:In the present study we aimed to explore the role of tyrosine kinase receptor, RET, in promoting breast cancer brain metastasis. Using patient-derived brain metastatic models, we found RET significantly enriched in brain metastasis originating from estrogen receptor positive breast cancer where it played a key role in promoting cancer cell adhesion, survival, and outgrowth in the brain.
Project description:Breast tumors are produced by an uncontrollable cell proliferation mechanism and can be classified as benign (TMB) or malignant (TMM). TMM or breast cancer is the neoplasia with the highest incidence and mortality in Mexican women. Over time, some types of TMB can transform into a TMM. However, the mechanisms involved in such processes remain elusive and limited studies have examined the molecular differences between TMB and TMM. Hence, the aim of this study was to evaluate and compare the proteomic profile of TMB (n = 10) and TMM (n = 6) of Mexican women.
Project description:Breast cancer is the leading type of cancer in women. Breast cancer brain metastasis is considered as an essential issue in breast cancer patients. Membrane proteins play important roles in breast cancer brain metastasis that contributes to the cell adhesion and penetration of blood-brain barrier. To achieve a deeper insight of the mechanism of breast cancer brain metastasis, liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed to analyze the enriched membrane proteomes from six different breast cancer cell lines. Quantitative proteomic data of all cell lines were compared with MDA-MB-231BR which has the specific brain metastasis capacity. 1239 proteins were identified and 990 were quantified with more than 70% of membrane proteins in all cell lines. Each cell line can be separated apart from others in PCA. Ingenuity pathway analysis (IPA) supported the high brain metastatic ability of 231BR and suggested importance of the up-regulation of integrin proteins and down-regulation of EPHA in brain metastasis. 28 proteins were observed unique expression alteration in 231BR. The up-regulation of NPM1, hnRNP Q, hnRNP K and eIF3l and the down-regulation of TUBB4B and TUBB were observed to be associated with the brain metastasis cell line and may contributes to the breast cancer brain metastasis.
Project description:Advanced breast cancer is characterised by enhanced tumour adaptability to therapeutic pressure and the metastatic microenvironment. Transcriptome differences in 14 primary breast tumour samples (n = 14 samples) are uncovered through this comparative RNA-seq analysis of patients that responded well to therapy (n = 7) and patients who had disease recurrence on endocrine treatment (n = 7). RNA sequencing data is deposited as log2 transformed median-of-ratios (DESeq2) normalised counts gene expression values (44934 genes IDs; n = 14 tumour samples).
Project description:Brain metastasis is one of the most feared complications of cancer and the most common intracranial malignancy in adults. Its underlying mechanisms remain unknown. From breast cancer patients with metastatic disease we isolated cell populations that aggressively colonize the brain. Transcriptomic analysis of these cells yielded overlapping gene sets whose expression is selectively associated with brain metastasis. The expression of seventeen of these genes in primary breast tumors is associated with brain relapse in breast cancer patients. Some of these genes are also associated with metastasis to lung but not to liver, bone or lymph nodes, providing a molecular basis for the long-observed link between brain and lung metastasis. Among the functionally validated brain metastasis genes, the cyclooxigenase COX-2, the EGFR ligand HB-EGF, and the brain-specific 2-6 sialyltransferase ST6GALNAC5 mediate cancer cell passage through the blood-brain barrier. Other brain metastasis genes encode inflammatory factors and brain-specific proteolytic regulators, suggesting a multifaceted program for breast cancer colonization of the brain. Experiment Overall Design: 204 primary tumors from breast cancer patients with known site of relapse were studied, focussing on brain relapse versus other relapse. Identified genes were validated in this cohort.
Project description:Breast cancer brain metastasis has been recognized as one of the central issues in breast cancer research. Elucidation of the process and pathway that mediate this step is expected to provide important clues for a better understanding of breast cancer metastasis. Increasing evidence suggests that the aberrant glycosylation patterns greatly contribute to the cell invasion and cancer metastasis. Herein, we combined next generation RNA sequencing with liquid chromatograph-tandem mass spectrometry based proteomic and N-glycomic analysis from five breast cancer cell lines and one brain cancer cell line to investigate the possible mechanism of breast cancer brain metastasis. 24763 genes were identified including 14551 differentially expressed genes across six cell lines while proteomic analysis allowed the quantitation of 1096 differentially expressed proteins with approximately 83.8% proteins’ regulation matching their gene expression change. The genes/proteins associated with cell movement were highlighted in the breast cancer brain metastasis. Integrin signaling pathway and the up-regulation of α-integrin (ITGA2, ITGA3) associated with the brain metastatic process was shown through Ingenuity Pathway Analysis (IPA). Overall 91 glycosylation genes were selected from transcriptomic data and all exhibited differential expression. 12 glycogenes showed unique expression in 231BR. The regulation of these genes could result in an activation prediction of sialylation function in 231BR by ingenuity pathway analysis. In agreement with the changes of glycogenes, 60 N-glycans out of 63 identified exhibited differential expression among cell lines. The correlation of glycogenes and glycans revealed the importance of sialylation and sialylated glycans in breast cancer brain metastasis. Highly sialylated glycans, which were up-regulated in brain seeking cell line 231BR, probably contributes to brain metastasis.
Project description:Brain metastasis is one of the most feared complications of cancer and the most common intracranial malignancy in adults. Its underlying mechanisms remain unknown. From breast cancer patients with metastatic disease we isolated cell populations that aggressively colonize the brain. Transcriptomic analysis of these cells yielded overlapping gene sets whose expression is selectively associated with brain metastasis. The expression of seventeen of these genes in primary breast tumors is associated with brain relapse in breast cancer patients. Some of these genes are also associated with metastasis to lung but not to liver, bone or lymph nodes, providing a molecular basis for the long-observed clinical link between brain and lung metastasis. Among the functionally validated brain metastasis genes, the cyclooxygenase COX-2, the EGFR ligand HB-EGF, and the brain-specific α2-6 sialyltransferase ST6GALNAC5 mediate cancer cell passage through the blood-brain barrier. Other brain metastasis genes encode inflammatory factors and brain-specific proteolytic regulators, suggesting a multifaceted program for breast cancer colonization of the brain. Experiment Overall Design: Two different breast cancer cell lines, MDA-MB-231 and freshly isolated pleural effusion CN34 were used in this study. The MDA-MB-231 group contains three biological replicates of the parental, unselected population, and 4 brain metastatic isolates. CN34 contains 2 biological replicates of the parental, unselected population, and 4 brain metastatic isolates. In each case, the parental population was compared to the brain metastatic isolates to identify gene expression changes associated with the brain metastatic phenotype.