Leucine, an amino acid that the body needs for making protein, appears to have a surprising role in the development of resistance to tamoxifen in breast cancer that tests positive for the estrogen receptor.
Scientists from Harvard Medical School, in Boston, MA, recently made this "unexpected" discovery about estrogen receptor-positive (ER-positive) breast cancer in a study conducted with colleagues from other research centers.
In laboratory experiments, they also found that the cell surface protein SLC7A5, which helps cells to take in leucine, influences the response of ER-positive breast cancer cells to tamoxifen.
The study authors note, in a paper published in Nature, that "SLC7A5 was necessary and sufficient to confer resistance to tamoxifen treatment" and suggest that the protein could be a potential target for "overcoming resistance" to tamoxifen in ER-positive breast cancer.
In around three-quarters of breast cancers, the hormone estrogen helps the tumors grow and spread.
This is because the cancer cells, like healthy breast cells, have estrogen receptors that allow them to receive growth signals from the hormone.
Doctors commonly treat ER-positive breast cancer with the drug tamoxifen because it blocks the action of estrogen in the cancer cells.
Tamoxifen resistance and leucine
However, while ER-positive breast cancers may respond to tamoxifen, in many cases they develop resistance to the drug, raising the risk of recurrence and metastasis, or spread.
"Patients with ER-positive breast cancer who develop endocrine-resistant and metastatic cancer have very poor life expectancy," says lead study author Senthil K. Muthuswamy, Ph.D., an associate professor of medicine at Harvard Medical School.
Because there are limited alternative treatment options, the average survival of these patients is "usually less than 5 years," he adds.
Amino acids are the building blocks that the body uses to make proteins. There are 20 of them in all. Of these, nine are essential, that is, the body must source them from food because it cannot make them itself.
Leucine is an essential amino acid that is especially important for making muscle protein. In general, apart from maize, plant foods contain less leucine than foods from animal origin. Pork, fish, chicken, and beef are examples of foods that have higher levels of leucine.
Reducing leucine stopped tumor growth
The fact that cells cannot synthesize leucine gave the researchers the opportunity to explore the reaction of ER-positive breast cancer cells to different levels of the amino acid that they could control.
Laboratory experiments using cultures of ER-positive breast cancer cells from human samples showed that reducing leucine stopped tumor cell division, while increasing it promoted cell division.
Muthuswamy says that these results point to the possibility of developing dietary interventions to help those with ER-positive breast cancer.
However, he cautions that the findings do not "imply that animal proteins will enhance growth of breast cancer cells." All they show is that reducing leucine in the diet could be of benefit to people with ER-positive breast cancer.
He and his team have already started another study to find out whether restricting dietary leucine can reduce tumor growth or boost treatment response in a mouse model of ER-positive breast cancer.
The role of SLC7A5 in tamoxifen resistance
In a final set of experiments, the team examined the effect of leucine levels on ER-positive breast cancer cells that had developed resistance to tamoxifen. These experiments revealed that resistant cells continued to grow, even when leucine levels were low.
On closer examination, the scientists found that the tamoxifen-resistant cells had higher levels of SLC7A5. Higher levels of this ferrying protein were helping the cells to take in more leucine, even when it was scarce.
In a final set of tests on mice, the researchers found that blocking SLC7A5 caused the animals' ER-positive tumors to shrink.
"A properly controlled clinical study to assess clinical benefit of actively decreasing leucine intake in diet during treatment for ER-positive breast cancer will be of significant value because a positive outcome can provide a simple intervention strategy that can help us better care for [these] patients."
Senthil K. Muthuswamy, Ph.D.