Immaculate Reception: Mutations Tackle Hormone Blockers

Mechanism by which the Y537S mutation stabilizes the active conformation of ER in the absence of estradiol. A hydrogen bond forms between the serine (S537) and an aspartic acid (D531) that is also located in the ER hormone-binding domain.

Mechanism by which the Y537S mutation stabilizes the active conformation of ER in the absence of estradiol. A hydrogen bond forms between the serine (S537) and an aspartic acid (D531) that is also located in the ER hormone-binding domain.

First, scientists developed a way to thwart breast cancer, by blocking the estrogen receptor. Then breast cancer evolved a way to thwart scientists.

Now, science may be regaining the upper hand, at least for the moment. Several teams of researchers have learned how breast cancers – 70 percent of which depend, at least initially, on estrogen – acquire over time the ability to get by without that hormonal stimulus.

Somehow, probably by chance, cancer cells develop two key mutations in a crucial part of the estrogen receptor. These mutations flip the switch from off to on, with or without estrogen. This drives rapid tumor-cell growth.

Geoffrey Greene, PhD

Geoffrey Greene, PhD

“It’s all quite Darwinian,” said Geoffrey Greene, PhD, co-author of one of the studies. The tumor cells need estrogen to survive and grow. Drugs such as tamoxifen or aromatase inhibitors keep estrogen away. So, under the stress of prolonged deprivation, some tumor cells manage to acquire the precise mutations needed to fill that gap. The mutations convince cells they are constantly bathed in estrogen. So they multiply and spread.

Greene’s team, from the Ludwig Center for Metastasis Research at the University of Chicago, worked with colleagues led by Sarat Chandarlapaty, PhD, at Memorial Sloan-Kettering Cancer Center in New York. They studied metastatic tumors from 36 breast cancer patients who had relapsed after almost five years, on average, of hormonal therapy.

They found two consistent mutations in one particular gene – ESR1, part of the estrogen receptor – in 25 percent of those tumors. These two mutations slightly altered the shape of the pocket where estrogen would normally connect with the receptor.

They found nearly identical changes in 12 percent of patients from a different cohort of 42 patients. At the same time, a group from the University of Michigan found similar mutations in 6 of 11 patients with metastatic breast cancer. Both the MSK-UChicago and the Michigan studies were published Sunday, November 3, in Nature Genetics.

When the researchers looked back at tissues taken during a biopsy or surgery from the same patients years before, they found that the mutations were not present before estrogen-blocking treatment. Larger tissue collections from newly diagnosed patients also lacked the mutations. This suggests that the anti-estrogen therapy may have caused the mutations to develop, or at least, once they occurred, granted them a competitive advantage. The cells with those specific mutations grew rapidly, while cells without those mutations did not.

“This is the tumor’s way of evading hormonal therapy,” Dan Robinson, PhD, lead author of the Michigan study, told a reporter from The Scientist. “These mutations activate the estrogen receptor when there is no estrogen.”

In the last 20 years, drugs that disrupt estrogen’s actions have become frontline treatments for breast cancer. This approach was developed nearly 50 years ago by Elwood Jensen and colleagues at the University of Chicago’s Ben May Institute for Cancer Research. According to the Lasker Foundation, Jensen-inspired hormonal therapies such as tamoxifen have transformed the treatment of breast cancer patients in a way that “saves or prolongs more than a 100,000 lives annually.”

Through computer modeling, the MSK-UChicago team found that the mutations appear to alter the shape of the estrogen-binding site on the receptor. Still, the authors note, higher doses of receptor agonists like tamoxifen and fulvestrant could overwhelm even the altered version and might still benefit patients.

They also suggest that researchers may be able to treat resistant tumors that harbor these mutations by developing new drugs that block the receptor more fully than current compounds do.

Toy W., Shen Y., Won H., Green B., Sakr R.A., Will M., Li Z., Gala K., Fanning S. & King T.A. & (2013). ESR1 ligand-binding domain mutations in hormone-resistant breast cancer, Nature Genetics, DOI:

Robinson D.R., Wu Y.M., Vats P., Su F., Lonigro R.J., Cao X., Kalyana-Sundaram S., Wang R., Ning Y. & Hodges L. & (2013). Activating ESR1 mutations in hormone-resistant metastatic breast cancer, Nature Genetics, DOI:

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