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How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?

ABSTRACT: Lymph node status is one of the best prognostic factors in breast cancer, however, its association with distant metastasis is not straightforward. Here we compare molecular mechanisms of nodal and distant metastasis in molecular subtypes of breast cancer, with major focus on luminal A patients. We analyze a new cohort of 706 patients (MMCI_706) as well as an independent cohort of 836 primary tumors with full gene expression information (SUPERTAM_HGU133A). We evaluate the risk of distant metastasis, analyze targetable molecular mechanisms in Gene Set Enrichment Analysis and identify relevant inhibitors. Lymph node positivity is generally associated with NF-?B and Src pathways and is related to high risk (OR: 5.062 and 2.401 in MMCI_706 and SUPERTAM_HGU133A, respectively, p < 0.05) of distant metastasis in luminal A patients. However, a part (?15%) of lymph node negative tumors at the diagnosis develop the distant metastasis which is related to cell proliferation control and thrombolysis. Distant metastasis of lymph node positive patients is mostly associated with immune response. These pro-metastatic mechanisms further vary in other molecular subtypes. Our data indicate that the management of breast cancer and prevention of distant metastasis requires stratified approach based on targeted strategies.

SUBMITTER: Lapcik P

PROVIDER: S-EPMC7563588 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?

Lapcik Petr P Pospisilova Anna A Janacova Lucia L Grell Peter P Fabian Pavel P Bouchal Pavel P

Cancers 20200916 9

Lymph node status is one of the best prognostic factors in breast cancer, however, its association with distant metastasis is not straightforward. Here we compare molecular mechanisms of nodal and distant metastasis in molecular subtypes of breast cancer, with major focus on luminal A patients. We analyze a new cohort of 706 patients (MMCI_706) as well as an independent cohort of 836 primary tumors with full gene expression information (SUPERTAM_HGU133A). We evaluate the risk of distant metastas ...[more]

PMID: 32947901

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Project description:Metastasis is the main cause of breast cancer?related mortalities. The present study aimed to uncover the relevant molecular mechanisms of breast cancer metastasis and to explore potential biomarkers that may be used for prognosis. Expression profile microarray data GSE8977, which contained 22 stroma samples (15 were from normal breast and 7 were from invasive ductal carcinoma tumor samples), were obtained from the Gene Expression Omnibus database. Following data preprocessing, differentially expressed genes (DEGs) were selected based on analyses conducted using the linear models for microarray analysis package from R and Bioconductor software. The resulting data were used in subsequent function and pathway enrichment analyses, as well as protein?protein interaction (PPI) network and subnetwork analyses. Transcription factors (TFs) and tumor?associated genes were also identified among the DEGs. A total of 234 DEGs were identified, which were enriched in immune response, cell differentiation and cell adhesion?related functions and pathways. Downregulated DEGs included TFs, such as the proto?oncogene SPI1, pre?B?cell leukemia homeobox 3 (PBX3) and lymphoid enhancer?binding factor 1 (LEF1), as well as tumor suppressors (TSs), such as capping actin protein, gelsolin like (CAPG) and tumor protein p53?inducible nuclear protein 1 (TP53INP1). Upregulated DEGs also included TFs and tumor suppressors, consisting of transcription factor 7?like 2 (TCF7L2) and pleiomorphic adenoma gene?like 1 (PLAGL1). DEGs that were identified at the hub nodes in the PPI network and the subnetwork were epidermal growth factor receptor (EGFR) and spleen?associated tyrosine kinase (SYK), respectively. Several genes crucial in the metastasis of breast cancer were identified, which may serve as potential biomarkers, many of which were associated with cell adhesion, proliferation or immune response, and may influence breast cancer metastasis by regulating these function or pathways.

Dataset Information

How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?

Publications

How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?

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