Molecular Medicine Israel

Secrets of Breast Cancer Resistance

Nature (2012); Doi: 10.1038/nature10730.
C. Ross-Innes, et al.
“Differential oestrogen receptor binding is associated with clinical outcome in breast cancer”.

A new study shows that breast cancers that become resistant to hormone therapy have different patterns of estrogen receptor binding.

A cluster of breast cancer cells undergoing programmed cell death
A cluster of breast cancer cells undergoing programmed cell death

Breast cancers may become resistant to standard hormone therapy because the estrogen receptor becomes reprogrammed to bind to different spots in the genome, according to a study publishing in Nature. The findings could provide clues for developing therapies to overcome resistance or diagnostics that could predict which patients are more likely to be resistant to hormone therapy.

“They have shown the pattern of binding is different between different types of tumors,” said medical endocrinologist Karin Dahlman-Wrightof the Karolinska Institute in Sweden, who was not involved in the study. “If we could change the pattern of binding, we could maybe make the tumors responsive to the endocrine therapy.”

Roughly three-quarters of breast cancers require an estrogen receptor to grow. The receptor is usually free-floating in the cytoplasm until it is bound by estrogen, at which point it travels into the nucleus where it binds to and activates the transcription of thousands of genes, fueling cancer growth.  Hormone therapy such as tamoxifen works to stop cancer growth by binding the receptor before estrogen, causing it to shut down all the genes it usually activates, thereby stopping cancer growth, said co-author Jason Carroll, a cancer biologist at Cancer Research UK.

Many breast cancers, however, become resistant to the therapy, and grow despite regular treatments. In the past few years, Carroll and colleagues have shown in cell lines derived from metastatic cancers that resistant cancers bind to different genes than non-resistant forms.

To see whether estrogen binding patterns also differed in actual patient tumors, the team examined tumor tissue from 17 breast cancer patients whose cancers were driven by the estrogen receptor. Using a special process called chromatin immunoprecipitation, the researchers isolated the estrogen receptors, as well as anything attached to the receptors, and sequenced those fragments to see which genes the estrogen receptor bound. They found that the estrogen receptors in patients with resistant cancers, who ultimately died, bound to different subsets of genes than receptors in sensitive cancers—apparently a set of genes that fuel growth even in the presence of hormone therapy.

But the question remains, how do the resistant cancers redirect the drug-bound estrogen receptors? One possibility is a protein called FOXA1, which has been shown in vitro to open DNA chromatin and initiate binding to the DNA. Indeed, the researchers found that levels of FOXA1 were enriched near the binding sites, and was also present in 95 percent of metastatic cancer samples that they tested. The researchers speculate that resistant cancers contain an altered FOXA1 protein that helps redirect the estrogen receptor to different sites in the genome, conferring resistance to hormone therapy.

It’s hard to say, however, whether FOXA1 is the master architect of the switch to resistance, or whether it is simply following the lead of some other protein, said Rachel Schiff, a cancer biologist at Baylor College of Medicine in Houston, who was not involved in the study.  To prove that, the researchers would need to show that removing FOXA1 from the mix could prevent the switch to resistance, she said.

If FOXA1 is the guilty party, however, targeting the protein with drugs early on in breast cancer therapy may one day help prevent resistance, said Vincent Giguere of McGill University, who wrote a Nature News and Views piece about the paper. “If you can stop the reprogramming early, then the tumor will not go from a good outcome to a bad outcome.” If the findings can be validated in a larger cohort of tumor samples, he added, researchers could also use estrogen receptor binding patterns to predict outcome in patients.


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