The findings, from Baylor College of Medicine, are published in Cancer Research, a journal of the American Association for Cancer Research. The first author is Xuxu Gou.
“About 80% of all breast cancers depend on the hormone estrogen to grow. Estrogen promotes tumor growth by binding to the ER,” said corresponding author Matthew J. Ellis, M.D., Ph.D., professor and director of the Lester and Sue Smith Beast Center at Baylor College of Medicine.
Disrupting the estrogen-ER interaction is a key therapeutic approach. Drugs such as tamoxifen and fulvestrant target the ER this way, but tumor cells learn to evade this attack and become resistant to these drugs.
This team used genomics and transcriptomics to annotate 20 mouse models of ER+ patient-derived tumors that demonstrated different degrees of dependence on estrogen for growth. In this data set, a 24-gene signature detected the presence of an active ESR1 fusion and also common point mutations in ESR1. These findings were replicated in data from a human metastatic breast cancer cohort. The team has dubbed their 24 gene signature the MOTERA score for “Mutant or Translocated Estrogen Receptor Alpha.”
The authors hope these findings can be used to guide physicians in more personalized treatment selection.
“One of the predominant ways ER+ breast cancer cells evade treatment is by creating mutant ERs that no longer can be recognized and targeted by ER-targeting cancer drugs,” said Gou, a graduate student in the Ellis Lab.
The team has been studying ESR1 gene translocations, which refer to the ER gene swapping a part of its sequence with genetic information from another gene. ER gene translocations create chimeric ER proteins, meaning the protein contains only half of the ER protein and the other half comes from different protein. Some of the ER chimeras are extreme versions of mutant ERs because the drug-binding region, which is the same region estrogen binds to, is completely replaced with a region derived from another protein, to which neither the drug nor estrogen can bind. These ER chimeras trigger cancer activity in the absence of hormone.
“Not all ER translocations were active – some drive metastasis and resistance to treatment, but others do not,” Gou said. “To be able to determine whether any particular ESR1translocation can promote disease progression, we developed a diagnostic genetic signature that detects the presence of an active ESR1 chimeric protein.”
“In the future, a patient’s cancer cells could be analyzed and, once the MOTERA score indicates the presence of an ER mutation or translocation, then the tumor cells would be further studied to more precisely determine what kind of ER mutant or translocation is present. This would help guide the selection of a personalized, optimal treatment,” said co-author, Charles E. Foulds, assistant professor at Baylor’s Lester and Sue Smith Breast Center.