An Essential Gene Signature of Breast Cancer Metastasis Reveals Targetable Pathways

Authors

Yiqun Zhang
Fengju Chen
Marija Balic
Chad J Creighton

Publication Date

6-12-2024

Journal

Breast Cancer Research

DOI

10.1186/s13058-024-01855-0

PMID

38867323

PMCID

PMC11167932

PubMedCentral® Posted Date

6-12-2024

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Humans, Breast Neoplasms, Female, Gene Expression Regulation, Neoplastic, Neoplasm Metastasis, Gene Expression Profiling, Transcriptome, Biomarkers, Tumor, Genes, Essential, Cell Line, Tumor, Signal Transduction, Prognosis

Abstract

BACKGROUND: The differential gene expression profile of metastatic versus primary breast tumors represents an avenue for discovering new or underappreciated pathways underscoring processes of metastasis. However, as tumor biopsy samples are a mixture of cancer and non-cancer cells, most differentially expressed genes in metastases would represent confounders involving sample biopsy site rather than cancer cell biology.

METHODS: By paired analysis, we defined a top set of differentially expressed genes in breast cancer metastasis versus primary tumors using an RNA-sequencing dataset of 152 patients from The Breast International Group Aiming to Understand the Molecular Aberrations dataset (BIG-AURORA). To filter the genes higher in metastasis for genes essential for breast cancer proliferation, we incorporated CRISPR-based data from breast cancer cell lines.

RESULTS: A significant fraction of genes with higher expression in metastasis versus paired primary were essential by CRISPR. These 264 genes represented an essential signature of breast cancer metastasis. In contrast, nonessential metastasis genes largely involved tumor biopsy site. The essential signature predicted breast cancer patient outcome based on primary tumor expression patterns. Pathways underlying the essential signature included proteasome degradation, the electron transport chain, oxidative phosphorylation, and cancer metabolic reprogramming. Transcription factors MYC, MAX, HDAC3, and HCFC1 each bound significant fractions of essential genes.

CONCLUSIONS: Associations involving the essential gene signature of breast cancer metastasis indicate true biological changes intrinsic to cancer cells, with important implications for applying existing therapies or developing alternate therapeutic approaches.

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