A gene sequence explains the causes of treatment resistance in breast cancer

Nov, 2021 - By SMI

A gene sequence explains the causes of treatment resistance in breast cancer

A multi-institutional research team led by Baylor College of Medicine scientists has uncovered a genetic signature that could detect drivers of bad results in advanced estrogen-receptor-positive breast cancer, potentially leading to tailored treatment in patients.

The 24-gene signature reveals the existence of ER gene mutations and translocations, which give the tumor the potential to create independently of estrogen and so make it resistant to current therapies aimed at interrupting estrogen-fueled growth of cancer cells. The findings propose a new technique for refining breast cancer detection, which could aid in the selection of tumor-specific therapy.

The researchers have been exploring ESR1 gene translocations, which occur when the ER gene swaps a portion of its structure with the genetic code from another gene. ER gene translocations result in chimeric ER proteins, which contain just half of the ER protein and the other half from a variety of proteins. Some of the ER chimeras are severe variants of mutant ERs in which the drug-binding area, which is also the region to which estrogen binds, has been fully replaced with a region generated from another protein, to where neither the medication nor estrogen can bind. In the absence of hormones, these ER chimeras activate cancer.

The scientists used genomes and transcriptomics to annotate 20 murine models of ER+ patient-derived tumors that revealed varying degrees of need on estrogen for growth, with funding from the National Cancer Institute's PDXnet initiative. A 24-gene signature confirms the existence of an active ESR1 fusion in this data set, but also prevalent point mutations in ESR1. These results were observed in a human metastatic breast cancer cohort.

The results are important in the field of precision medicine because they can reveal specific characteristics of the tumor that can help doctors choose more treatment options.

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