Researchers at the Beth Israel Deaconess Medical Center (BIDMC) Cancer Center have uncovered an unexpected link between the essential amino acid leucine and tamoxifen resistance in estrogen-receptor positive (ER+) breast cancer, which hint that patients may benefit from reducing how much animal protein they eat. Studies headed by Senthil K. Muthuswamy, PhD, and colleagues, in cultured cells and in mice, indicated that reducing leucine levels suppresses ER+ breast cancer cell proliferation, and showed that a key leucine carrier that is responsible for importing the amino acid into cells acts to regulate response to tamoxifen.

“Our findings in the lab demonstrate that decreasing leucine levels suppresses proliferation of tumor cells, whereas increasing leucine enhances it,” commented Muthuswamy, who is director of the cell biology program and deputy director of translational research in the Cancer Research Institute at BIDMC. “Furthermore, the findings open up the possibility that a low-leucine diet could be beneficial for patients with ER+ breast cancer … Because animal proteins have a higher amount of leucine compared to plant proteins, this study begins to identify a diet intervention strategy to help patients with ER+ breast cancers.”

The team reported its findings in Nature, in a paper titled, “LLGL2 rescues nutrient stress by promoting leucine uptake in ER+ breast cancer.”

About one in eight women will develop breast cancer, and about 75% of cases are estrogen receptor positive cancers that need estrogen and/or progesterone to grow. This type of cancer is commonly treated using the endocrine therapy tamoxifen, which attaches to the hormone receptor in the cancer cells, blocking estrogen from binding. However, the treatment will frequently stop working as the cancer cells become tamoxifen resistant. “… the development of resistance to endocrine therapy and metastatic progression are leading causes of death for patients with ER+ disease,” the authors wrote. “Patients with ER+ breast cancer who develop endocrine-resistant and metastatic cancer have very poor life expectancy, usually less than five years survival, because they have limited treatment options available,” Muthuswamy noted.

The proteins in our bodies are made up of 20 amino acid building blocks. Nine of these amino acids, including leucine, are known as essential amino acids because our cells can’t make them from scratch, and so we have to obtain them from our food. Meat and fish are particularly rich sources of leucine.

Muthuswamy’s team manipulated leucine levels in cultures of ER+ breast cancer cells to see how cell growth would be affected. They found that reducing leucine held back ER+ breast cancer cell division, while increasing leucine levels tenfold increased cell proliferation. The researchers also found that cells that had been induced to become resistant to tamoxifen could still proliferate even when levels of leucine were low. Further studies showed that the tamoxifen-resistant cells carried high levels of the leucine transporter SCL7A5 (also referred to as LAT1 (L-type amino acid transporter), a cell surface protein that carries the amino acid into cells. Increasing levels of SLC7A5 in cultured ER+ MCF-7 breast cancer cells effectively allowed the cells to acquire more leucine, and their resistance to tamoxifen increased. “Strikingly, overexpression of SLC7A5 in parental MCF-7 cells was sufficient to induce tamoxifen resistance,” the investigators noted. Conversely, chemically inhibiting SLC7A5 led to ER+ tumor in live mouse models.

Interestingly, the researchers wrote, SLC7A5 is overexpressed in multiple cancers, including breast cancer. An analysis of patient data showed that high expression of SLC7A5 “correlated with poor survival in 799 patients with ER+ breast cancer who had been treated with tamoxifen,” they commented. The BIDMC findings that SLC7A5 is necessary for and also sufficient to confer resistance to tamoxifen therapy have highlighted SLC7A5 as “a potential therapeutic target for overcoming resistance to endocrine treatments in breast cancer.”

Senthil K. Muthuswamy, PhD, of the Cancer Center at Beth Israel Deaconess Medical Center. [BIDMC]
The reported results also offer up completely new insights into tumor cell biology, the researchers noted, and indicate that cells adapt to nutrient stress by increasing surface SLC7A5. “Before this research, there was no reason to expect that estrogen biology has anything to do with affecting intracellular levels of leucine in cells,” said first author, Yasuhiro Saito, PhD, a research fellow in the department of medicine and pathology at BIDMC. “We have uncovered a new area of estrogen receptor biology, which will lead to new strategies to help patients with endocrine-resistant breast cancer.”

Prior research has reported that reducing intake of leucine can improve metabolic health, Muthuswamy noted. Decreasing total dietary protein has also been linked with better metabolic health and lifespan in rodent studies, while human and mouse studies have demonstrated that a low leucine diet can have health benefits. Although restricting protein intake to the point that it doesn’t meet daily nutrient requirements is not advisable, Muthuswamy suggested that a diet made-up of low-leucine plant proteins may be a better alternative for patients with ER+ breast cancer.

The researchers are not suggesting that diets high in leucine act to fuel breast cancer, Muthuswamy noted. “Our research does not imply that animal proteins will enhance growth of breast cancer cells—only that lowering leucine levels can be beneficial for patients diagnosed with ER+ breast cancer … A properly controlled clinical study to assess clinical benefit of actively decreasing leucine intake in diet during treatment for ER+ breast cancer will be of significant value because a positive outcome can provide a simple intervention strategy that can help us better care for patients with endocrine-sensitive and resistant breast cancer.”

The BIDMC team is already investigating whether a diet low in leucine can help to prevent ER+ tumor growth or boost response to therapy in mouse models.

 

 

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