It is estimated that one in eight women in the United States will suffer from breast cancer in her lifetime. Most of these cancerous tumors rely on the hormone estrogen to grow. Breast cancer tumors that are estrogen-receptor positive (ER+) are often treated with tamoxifen. This drug blocks the hormone that fuels the tumor. Nevertheless, many tumors eventually become resilient to tamoxifen, allowing the disease to spread or recur.
Overview Of The Study
Scientists at the Cancer Center at Beth Israel Deaconess Medical Center have discovered a surprising link between tamoxifen resistance and the essential amino acid leucine in ER+ breast cancer. This hints that patients may be better off reducing the amount of animal protein they consume.
Research on cultured cells in mice, led by Senthil Muthiswamy, Ph.D., and colleagues, indicated that decreasing leucine levels prevents ER+ breast cancer cell growth. Results also show that a key leucine carrier that is responsible for transporting the amino acid into cells controls response to tamoxifen.
Muthuswamy, who is the deputy director of translational research and director of the cell biology program in the same institute, explains, “Our findings in the lab demonstrate that decreasing leucine levels suppresses proliferation of tumor cells, whereas increasing leucine enhances it.”
“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 authors reported their findings in Nature, in a journal titled, “LLGL2 rescues nutrient stress by promoting leucine uptake in ER+ breast cancer.”
Consequence Of Resistance To Therapy
About 75 percent of breast cancer cases in women are ER+ diseases that need estrogen and/progesterone to develop. This type of cancer is often treated using endocrine therapy tamoxifen. The drug clings to the hormone receptor in the malignant cells, stopping estrogen from binding. This treatment becomes ineffective as the cancer cells turn impervious to tamoxifen.
The spread of cancer, as well as the growing resistance to endocrine therapy, will most likely result in the death of the patient. People with ER+ breast cancer who develop this drug resistance have an extremely short life expectancy. They usually expect less than five years to live as their treatment options become limited.
About 20 amino acid building blocks make up the protein in our bodies. Nine of these, including leucine, are called essential amino acids because our cells do not produce them naturally. Instead, we have to obtain them from our food. Leucine-rich food sources include fish and meat.
Manipulating Leucine Levels
The research team controlled leucine levels in cultures of ER+ breast cancer cells to find out how cell development would react. Results reveal that diminishing these levels held back the cell division of the disease. On the other hand, adding more leucine led to the spread of malignant cells. The scientists also discovered that cells that had been manipulated to become tamoxifen-resilient could still multiply even when levels of the particular essential amino acid were low.
Further investigation showed that the resistant cells had high levels of the leucine transporter SCL7A5, also known as LAT1 or L-type amino acid transporter. This is a cell surface molecule that carries the amino acid into cells. Surging the levels of SLC7A5 in test sample ER+ MCF-7 breast cancer cells successfully allowed the cells to obtain more leucine. This increased the cells’ resistance to tamoxifen.
The scientists noted that the effect of overexpressing SLC7A5 in parental MCF-7 cells was striking. They explained that this procedure was enough to induce drug resistance. Conversely, chemically obstructing SLC7A5 resulted in ER+ tumor in live mouse subjects.
New Insights On Tumor Cell Biology
Fascinatingly, the team reported that SLC7A5 is highly expressed in various cancers, including breast cancer. A study of patient data revealed that overexpression of SLC7A5 is linked to a low survival rate in 799 ER+ breast tumor patients who had gone tamoxifen therapy. The institute’s findings that SLCA5 is important for, and also enough to confer resilience to treatment, have emphasized that the leucine transporter could be a potential target for therapy. This feat may overcome resistance to endocrine treatments against the disease.
The outcome of the experiments also opens completely new pathways into tumor cell biology. The team noted that this information could mean that cells adapt to nutrient stress by increasing surface SLC7A5. Before this study, nobody suspected that estrogen biology had anything to do with intracellular levels of leucine in cells.
First author Yasuhiro Saito, Ph.D., a researcher in the department of medicine and pathology from the said cancer center, says, “We have uncovered a new area of estrogen receptor biology, which will lead to new strategies to help patients with endocrine-resistant breast cancer.”
A Potential Benefit Of Low-Leucine Diets
Earlier studies have shown that reducing leucine intake can improve metabolic health. Cutting total dietary protein has also been associated with a longer lifespan and better health in rodent testing. Prior human and mouse research has confirmed that a low-leucine diet can have health benefits. However, a person’s daily nutrient requirements should still be met. It is not recommended to completely restrict protein intake to the point that you neglect your body’s daily needs. Muthuswamy advises ER+ breast cancer patients to choose low-leucine plant proteins instead.
In conclusion, the authors do not suggest that diets high in leucine drive breast cancer. Muthuswamy cleared that their study does not mean to imply that animal proteins enhance breast cancer cell growth – only that lowering leucine levels can lead to health benefits for those diagnosed with ER+ breast cancer.
“A properly controlled clinical study to assess the 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 same team is currently working on a study to know whether a diet low in leucine can boost response to therapy or help prevent ER+ tumor growth in mouse models.