Abstract
Intratumor morphological heterogeneity reflects patterns of invasive growth and is an indicator of the metastatic potential of breast cancer. In this study, we used this heterogeneity to identify molecules associated with breast cancer invasion and metastasis. The gene expression microarray data were used to identify genes differentially expressed between solid, trabecular, and other morphological arrangements of tumor cells. Immunohistochemistry was applied to evaluate the association of the selected proteins with metastasis. RNA-sequencing was performed to analyze the molecular makeup of metastatic tumor cells. High frequency of metastases and decreased metastasis-free survival were detected in patients either with positive expression of KIF14 or Mieap or negative expression of EZR at the tips of the torpedo-like structures in breast cancers. KIF14- and Mieap-positive and EZR-negative cells were mainly detected in the torpedo-like structures of the same breast tumors; however, their transcriptomic features differed. KIF14-positive cells showed a significant upregulation of genes involved in ether lipid metabolism. Mieap-positive cells were enriched in genes involved in mitophagy. EZR-negative cells displayed upregulated genes associated with phagocytosis and the chemokine-mediated signaling pathway. In conclusion, the positive expression of KIF14 and Mieap and negative expression of EZR at the tips of the torpedo-like structures are associated with breast cancer metastasis.
Highlights
Invasion is the first step towards cancer metastasis [1,2]
Using the gene expression data of breast cancer morphological structures (GEO, GSE80754), Usinggenes the gene expression data of breast cancer invasion morphological (GEO, GSE80754), we selected potentially associated with cancer basedstructures on the following criteria: we selected genes potentially associated with cancer invasion based on the following
Our results indicate that positive expression of KIF14 and Mitochondria-eating protein (Mieap) and negative expression of EZR at the tips of the torpedo-like structures are significantly associated with breast cancer metastasis
Summary
Invasion is the first step towards cancer metastasis [1,2]. During the invasion, cancer cells penetrate surrounding tissue and intravasate into blood vessels, where they spread via blood flow to Cancers 2020, 12, 1909; doi:10.3390/cancers12071909 www.mdpi.com/journal/cancersCancers 2020, 12, 1909 distant organs, extravasate and form the micrometastases, which outgrow into macroscopic metastases [1].According to the classical concept, there are two modes of cancer cell invasion: single-cell (individual) and collective invasion [3]. Invasion is the first step towards cancer metastasis [1,2]. Cancers 2020, 12, 1909 distant organs, extravasate and form the micrometastases, which outgrow into macroscopic metastases [1]. According to the classical concept, there are two modes of cancer cell invasion: single-cell (individual) and collective invasion [3]. Single-cell invasion is strongly associated with a process of epithelial–mesenchymal transition (EMT), during which cancer cells lose epithelial characteristics and obtain mesenchymal traits, namely increased motility and invasiveness [7,8]. Cancer cells are undergoing a partial EMT when mesenchymal traits are acquired but epithelial features and intercellular contacts are not lost [6,9]. Invading cells can be part of large tumor masses or be formed into groups with the different architectural organization [3,10]
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