CRISPR-Cas9 Mouse Xenograft Study Shows ESR1 Mutations Facilitate Metastasis

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Estrogen receptor gene mutations facilitate tumor metastasis.
Estrogen receptor gene mutations facilitate tumor metastasis.

Estrogen receptor gene (ESR1) mutations facilitate tumor metastasis, according to findings from preclinical lab experiments presented at the 2016 San Antonio Breast Cancer Symposium.1

ESR1 mutations are a bona-fide mechanism of acquired hormone resistance,” reported lead study author Suzanne A.W. Fuqua, PhD, of the Baylor College of Medicine in Houston, Texas. “This is the first preclinical evidence that ESR1 mutations also enhance tumor progression and metastatic behavior.”

ESR1 mutations are common in metastatic breast tumors following hormone therapy, but their role in metastasis has been unclear.

The study authors used CRISPR-Cas9 gene editing to create ESR1 Y537S homozygous “knock-in” mutations in MCF-7 cell lines for use in tumor xenograft studies with mice. Protein-DNA interactions were analyzed with ChIP-Seq and transcriptome-profiling analyses were performed.

“Transcriptome profiling revealed elevated expression of Hallmark pathways, including EMT [epithelial-mesenchymal transition] and estrogen-regulated gene expression,” Dr Fuqua reported.

EMT has been implicated in tumor metastasis, she noted.

The Y537S estrogen receptor mutation drove distant metastasis in ER-positive breast cancer cell xenografts. In cell enrichment experiments, the percentage of mutant cells within a xenograft tumor was associated with the frequency of metastasis to lung tissue.

Tamoxifen failed to reduce primary mutant tumor cell growth but did reduce the incidence of metastasis, Dr Fuqua reported.

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“That was a big surprise,” she said. “Tamoxifen was very effective at inhibiting macro-mets in Y537S.”

ESR1 mutations are “potential new predictive” markers for metastatic breast cancer and hormone therapy decision-making, she said.

Reference

  1. Fuqua SA, Gu G, Rechoum Y, et al. The Y537S ESR1 mutation is a dominant driver of distant ER-positive breast cancer metastasis. Paper presented at: 39th San Antonio Breast Cancer Symposium; Dec 2016; San Antonio, TX.

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