Dataset Information

FRY Impacts Breast Cancer Malignancy by Inducing an Enrichment of Genes with Tumor-Suppressive Functions and Affecting EMT Potential of Breast Cancer Cells

ABSTRACT: Breast cancer is a disease with diverse phenotypes, and while the progression of breast cancer from a localized lesion to metastatic disease is well understood clinically. Our previous study genetically linked the FRY gene with differential susceptibility to mammary carcinogenesis; however, little is known about the mechanistic insights of FRY in mammalian cells and breast cancer progression. Through RNA-Seq analysis of series of constructed cell lines based on highly malignant triple-negative human breast cancer cells MDA-MB-231, we show that enhanced FRY induces massive changes in gene expression, which favor signalings and molecules with tumor-suppressive functions and engage in promoting cell differentiation, maintaining the normal and histopathological characteristics of epithelial cells, and in regulating EMT potential of breast cancer cells. As a result, the proliferation, migration and invasion potentials of breast cancer cells are significantly inhibited both in vitro and in xenograft tumor models. Importantly, consistent with FRY’s anti-tumor progression role, decreased FRY protein levels are correlated with poorly differentiated and aggressive tumor phenotypes in the analysis of two clinically annotated breast cancer cohorts. Our results identify FRY’s potent tumor-suppressive role at the gene transcription and molecular function levels, providing a novel biomarker for breast cancer prognosis and a target for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112910 | GEO | 2019/05/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Tumor-initiating cells with reprogramming plasticity and/or de-differentiation attributes have been thought to initiate primary tumor development as well as to regenerate secondary tumors in metastatic organs; however, the molecular mechanisms are not fully understood. We previously found that breast tumor-initiating cell marker, CD44, directs multicellular aggregation and cluster formation of circulating tumor cells (CTCs), which further enhance stemness and survival of such cells, enabling metastatic colonization to the lungs. To further elucidate the molecular network underlying CTC cluster formation, we performed global proteomic profiling and discovered that the tetraspanin protein CD81, which is normally enriched in exosomes (small extracellular vesicles), is a new driver of cancer initiation and metastasis as a facilitator and target of CD44. Loss of CD81 compromises tumorigenicity and mammosphere formation of triple negative breast cancer (TNBC) cells. Assisted by machine learning-based algorithms and mutagenesis approach, we found that CD81 interacts with CD44 on the cellular membrane through their extracellular regions. Notably, genetic knockout of CD44 or CD81 results in loss of both CD81 and CD44 in secreted exosomes, a state which abolishes exosome-induced self-renewal of recipient cells, such as mammosphere formation. In addition, RNA sequencing analysis showed that CD81 knockdown up-regulates expression of a cell differentiation marker, SEMA7a, whose down-regulation partially rescues mammosphere formation inhibition by CD81 depletion. Clinically, CD81 expression was observed in >80% of CTCs and specifically enriched and co-expressed along with CD44 in clustered CTCs of breast cancer patients. Mimicing the phenotypes of CD44 deficiency, loss of CD81 also inhibited tumor cell aggregation and lung metastasis of TNBC in both human and mouse tumor models, supporting the clinical significance of CD81 in association with patient outcomes. Our study highlights a new driving role of CD81 in cancer exosome-induced stemness, clustered CTCs, and metastasis initiation of TNBC, reported for the first time to our knowledge.

Dataset Information

FRY Impacts Breast Cancer Malignancy by Inducing an Enrichment of Genes with Tumor-Suppressive Functions and Affecting EMT Potential of Breast Cancer Cells

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets