Immune-related transcriptomic landscape of primary tumors and lymph node metastasis of chemotherapy-naïve breast cancer patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE180186 | GEO | 2021/07/21
REPOSITORIES: GEO
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Project description:The lymphatic system is a common avenue for the spread of breast cancer cells and dissemination through it occurs at least as frequently as hematogenous metastasis. Approximately 75% of primary breast cancers are estrogen receptor (ER) positive and the majority of these maintain receptor expression as lymph node (LN) metastases. However, it is unknown if ER function is equivalent in cancer cells growing in the breast and in the LNs. We have developed a model to assess estrogen responsiveness in ER(+) breast tumors and LN metastases. Fluorescent ER(+) MCF-7 tumors were grown in ovariectomized nude mice supplemented with estradiol. Once axillary LN metastasis arose, estradiol was withdrawn (EWD), for 1 or 4 weeks, or continued, to assess estradiol responsiveness. On EWD, proliferation rates fell similarly in tumors and LN metastases. However, estradiol-dependent ER down-regulation and progesterone receptor induction were deficient in LN metastases, indicating that ER-dependent transcriptional function was altered in the LN. Cancer cells from estradiol-treated and EWD primary tumors and matched LN metastases were isolated by laser capture microdissection. Global gene expression profiling identified transcripts that were regulated by the tissue microenvironment, by hormones, or by both. Interestingly, numerous genes that were estradiol regulated in tumors lost estradiol sensitivity or were regulated in the opposite direction by estradiol in LN metastases. We propose that the LN microenvironment alters estradiol signaling and may contribute to local antiestrogen resistance. Keywords: Breast cancer lymph node metastasis, ER positive, MCF7, xenograft
2008-05-02 | GSE11317 | GEO
Project description:Cytotoxic chemotherapy is used to treat many thousands of patients across many cancer types annually. Recent studies have demonstrated that chemotherapy causes systemic response that can be exploited to promote cancer cell survival and dissemination, termed “chemotherapy-induced metastasis. However, there have been no studies investigating how chemotherapy alters the extracellular matrix of breast tumors, or if those changes might help to support metastatic dissemination. Here, we report the first characterization of the chemotherapy-treated breast cancer matrisome using the MMTV-PyMT transgenic mouse model of breast cancer. We identify distinct changes induced by different cytotoxic chemotherapies. In particular, we identify collagen IV as significantly associated with taxane-based chemotherapy treatment. Biological validation confirmed collagen IV as chemotherapy-associated and identified collagen IV-driven Src and FAK signaling as important mediators of invasion in the post-chemotherapy tumor microenvironment.
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Project description:The lymphatic system is a common avenue for the spread of breast cancer cells and dissemination through it occurs at least as frequently as hematogenous metastasis. Approximately 75% of primary breast cancers are estrogen receptor (ER) positive and the majority of these maintain receptor expression as lymph node (LN) metastases. However, it is unknown if ER function is equivalent in cancer cells growing in the breast and in the LNs. We have developed a model to assess estrogen responsiveness in ER(+) breast tumors and LN metastases. Fluorescent ER(+) MCF-7 tumors were grown in ovariectomized nude mice supplemented with estradiol. Once axillary LN metastasis arose, estradiol was withdrawn (EWD), for 1 or 4 weeks, or continued, to assess estradiol responsiveness. On EWD, proliferation rates fell similarly in tumors and LN metastases. However, estradiol-dependent ER down-regulation and progesterone receptor induction were deficient in LN metastases, indicating that ER-dependent transcriptional function was altered in the LN. Cancer cells from estradiol-treated and EWD primary tumors and matched LN metastases were isolated by laser capture microdissection. Global gene expression profiling identified transcripts that were regulated by the tissue microenvironment, by hormones, or by both. Interestingly, numerous genes that were estradiol regulated in tumors lost estradiol sensitivity or were regulated in the opposite direction by estradiol in LN metastases. We propose that the LN microenvironment alters estradiol signaling and may contribute to local antiestrogen resistance. Experiment Overall Design: 10 samples, including 3 each of estrogen and estrogen withdrawn axillary lymph nodes and 2 each of estrogen and estrogen withdrawn primary mammary gland tumors.
2008-06-11 | E-GEOD-11317 | biostudies-arrayexpress
Project description:n breast cancer (BC), detecting low volumes of axillary lymph node (ALN) metastasis pre-operatively is difficult and novel biomarkers are needed. We recently showed that patient-derived ALNs can be sustained ex-vivo using normothermic perfusion. We now compare reactive (tumour-free; n = 5) and macrometastatic (containing tumour deposits >2mm; n = 4) ALNs by combining whole section multiplex immunofluorescence with TMT-labelled LC-MS/MS of the circulating perfusate. Macrometastases contained significantly fewer B- and T-cells (CD4+/CD8+/regulatory) than reactive nodes (p = 0.02). Similarly, pathway analysis of the perfusate proteome (119/1453 proteins significantly differentially expressed) showed that immune function was diminished in macrometastases in favour of ‘extracellular matrix degradation’; only ‘neutrophil degranulation’ was preserved. Qualitative comparison of the perfusate proteome to that of node-positive pancreatic and prostatic adenocarcinoma also highlighted ‘neutrophil degranulation’ as a contributing factor to nodal metastasis. Thus, metastasis-induced changes in the REPLICANT perfusate proteome are detectable, and could facilitate biomarker discovery.
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Project description:To identify the mRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) involved in the pathogenesis of breast cancer, we performed the whole transcriptome sequencing. The whole transcriptome sequencing was performed with three breast cancer tissues with or without lymph node metastasis in each group, respectively. The results showed that 728 mRNAs, 131 lncRNAs, and 144 circRNAs were differentially expressed in lymph node metastasis group and no lymph node metastasis group (fold change≥2, p<0.05). These data indicate that dysregulation of mRNAs, lncRNAs, and circRNAs may contribute to breast cancer progression.
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Project description:Metastasis remains the leading cause of death in breast cancer. However, little is known about the dynamic changes during the dissemination of breast cancer. Here, we generate single-cell RNA and spatial transcriptome of primary tumors and paired metastatic lymph nodes in 4 breast cancer patients. We identified a disseminated cancer cell cluster with high levels of oxidative phosphorylation (OXPHOS). We also noticed the transition between glycolysis and OXPHOS when dissemination initiates. Furthermore, this distinct cell cluster is distributed along the tumor’s leading edge.
2023-02-19 | GSE225600 | GEO
Project description:Lymph node involvement is a major prognostic variable in breast cancer. Whether the molecular mechanisms that drive breast cancer cells to colonize lymph nodes are shared with their capacity to form distant metastases is yet to be established. In a transcriptomic survey aimed at identifying molecular factors associated with lymph node involvement of ductal breast cancer, we found that luminal differentiation, assessed by the expression of estrogen receptor (ER) and/or progesterone receptor (PR) and GATA3, was only infrequently lost in node-positive primary tumors and in matched lymph node metastases. The transcription factor GATA3 critically determines luminal lineage specification of mammary epithelium and is widely considered a tumor and metastasis suppressor in breast cancer. Strong expression of GATA3 and ER in a majority of primary node-positive ductal breast cancer was corroborated by quantitative RT-PCR and immunohistochemistry in the initial sample set, and by immunohistochemistry in an additional set from 167 patients diagnosed of node-negative and positive primary infiltrating ductal breast cancer, including 102 samples from loco-regional lymph node metastases matched to their primary tumors, as well as 37 distant metastases. These observations suggest that loss of luminal differentiation is not a major factor driving the ability of breast cancer cells to colonize regional lymph nodes. The transcriptomic study comprises 16 samples from Lymph node metastasis from infiltrating ductal breast carcinoma, 18 samples from Primary node-positive infiltrating ductal,7 samples from Primary node-negative infiltrating ductal and 3 samples from Unaffected lymph node were included. Their RNA was isolated and prepared for hybridization to human Affymetrix GeneChip arrays.
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Project description:Immune-related transcriptomic landscape of primary tumors and lymph node metastasis of chemotherapy-naïve breast cancer patients
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Project description:The lungs are a frequent target of metastatic breast cancer cells, but the underlying molecular mechanisms are unclear. All existing data were obtained either using statistical association between gene expression measurements found in primary tumors and clinical outcome, or using experimentally derived signatures from mouse tumor models. Here, we describe a distinct approach that consists to utilize tissue surgically resected from lung metastatic lesions and compare their gene expression profiles with those from non-pulmonary sites, all coming from breast cancer patients. We demonstrate that the gene expression profiles of organ-specific metastatic lesions can be used to predict lung metastasis in breast cancer. We identified a set of 21 lung metastasis-associated genes. Using a cohort of 72 lymph node-negative breast cancer patients, we developed a six-gene prognostic classifier that discriminated breast primary cancers with a significantly higher risk of lung metastasis. We then validated the predictive ability of the six-gene signature in 3 independent cohorts of breast cancers consisting of a total of 721 patients. Finally, we demonstrated that the signature improves risk stratification independently of known standard clinical parameters and a previously established lung metastasis signature based on an experimental breast cancer metastasis model. Experiment Overall Design: We used microarrays to identify lung metastasis-related genes in a series of 23 patients with breast cancer metastases. No replicate, no reference sample.
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