Research conducted at Beth Israel Deaconess Medical Center (BIDMC) Cancer Center links resistance to the breast cancer drug Tamoxifen with high levels of the essential amino acid leucine. The research also suggests that a reducing leucine levels through dietary changes could help to suppress estrogen-receptor positive (ER+) breach cancer proliferation.
Senthil K. Muthuswamy, PhD, and his team demonstrated that in cultured cells and mice, decreasing leucine levels suppressed tumor cell proliferation and increasing leucine levels enhanced proliferation.
Breast cancer is one of the most common cancers. One in eight women will develop breast cancer at some point in their lives and 75% of breast cancers are ER+.
ER+ breast cancers require either estrogen or progesterone to proliferate. Tamoxifen is a form of endocrine therapy and is one of the most effective treatments for ER+ breast cancer. The drug binds to the hormone receptor on cancer cells and stops estrogen from binding.
While the treatment is effective, oftentimes Tamoxifen resistance develops and the treatment stops working. Tamoxifen resistance often proves fatal. Patients with endocrine therapy-resistant cancers rarely survive more than five years as there are few other treatment options available.
In addition to identifying the link between leucine levels and cancer cell proliferation, they found high levels of the leucine transporter SCL7A5 in cells that were resistant to Tamoxifen.
When the researchers increased the levels of SCL7A5 in cultured ER+ breast cancer cells, more leucine was transported into the cells and resistance to Tamoxifen increased. The researchers note that in addition to ER+ breast cancers, SCL7A5 overexpression is common in other several other cancers.
“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 Yasuhiro Saito, PhD, first author of the study. “We have uncovered a new area of estrogen receptor biology, which will lead to new strategies to help patients with endocrine-resistant breast cancer.”
The research suggests SCL7A5 could be a potential target for overcoming resistance to endocrine treatments in breast cancer patients, while switching to a diet low in animal protein, the main source of leucine in the diet, could help patients with ER+ breast cancers.
The researchers point out that their research does not indicate animal proteins enhance the growth of breast cancer cells, only that lowering levels of dietary leucine could be beneficial for patients who have developed ER+ breast cancer. Also, leucine is an essential amino acid and cannot be produced by the body. Eliminating all dietary sources of leucine to the point where insufficient levels are consumed to meet metabolic requirements would not be advisable.
The findings are detailed in the paper – LLGL2 rescues nutrient stress by promoting leucine uptake in ER+ breast cancer – which was recently published in the journal Nature. DOI: 10.1038/s41586-019-1126-2