Elevated BCAA Suppresses the Development and Metastasis of Breast Cancer

Abstract

Branched-chain amino acids (BCAAs) are the three essential amino acids including leucine, isoleucine, and valine. BCAA metabolism has been linked with the development of a variety of tumors. However, the impact of dietary BCAA intake on breast tumor progression and metastasis remains to be fully explored. Here, we unexpectedly find that the elevated BCAA, either in the genetic model or via increasing dietary intake in mice, suppresses the tumor growth and lung metastasis of breast cancer. The survival analysis shows that BCAA catabolic gene expression is strongly associated with long-term oncological outcomes in patients with breast cancer. In Pp2cm knockout mice in which BCAAs accumulate due to the genetic defect of BCAA catabolism, the breast tumor growth is suppressed. Interestingly, while the cell proliferation and tumor vasculature remain unaffected, more cell death occurs in the tumor in Pp2cm knockout mice, accompanied with increased natural killer (NK) cells. Importantly, increasing BCAA dietary intake suppresses breast tumor growth in mice. On the other hand, there are fewer lung metastases from primary breast tumor in Pp2cm knockout mice and the high BCAA diet-fed mice, suggesting high BCAA also suppresses the lung metastasis of breast cancer. Furthermore, low BCAA diet promotes lung colonization of breast cancer cells in tail vein model. The migration and invasion abilities of breast cancer cells are impaired by high concentration of BCAA in culture medium. The suppressed tumor metastasis and cell migration/invasion abilities by elevated BCAA are accompanied with reduced N-cadherin expression. Together, these data show high BCAA suppresses both tumor growth and metastasis of breast cancer, demonstrating the potential benefits of increasing BCAA dietary intake in the treatment of breast cancer.

Serum amino acids quantification by plasmonic colloidosome-coupled MALDI-TOF MS for triple-negative breast cancer diagnosis

“…Dysregulation of the metabolism of branched-chain amino acids (BCAAs) including leucine (Leu), valine (Val), and isoleucine (Ile) has been reported to be associated with specific cancer phenotypes. BCAAs can inhibit the growth and metastasis of tumor [ 31 ], thereby changes in the content of BCAAs can often reflect the systemic changes in cancer patients compared to healthy controls [ 32 ]. Jasbi et al.…”

Amino acid metabolic reprogramming in tumor metastatic colonization

“…It was reported that in breast cancer mouse models, less lung metastases were observed in the high BCAAs diet-fed mice. The mechanism is that high levels of BCAAs activated tumor-infiltrating NK cells in lung metastases ( 124 ). This study indicates that high BCAA may not promote the proliferation of cancer cells in lung metastases, but conversely inhibit lung metastasis by promoting the activity of tumor-infiltrating NK cells in lung metastases ( Figure 4 ).…”

Amino acids and their roles in tumor immunotherapy of breast cancer

“…Therefore, increasing BCAA uptake may be a practical dietary therapy for breast cancer. 25 Metabolic dysfunction is a hallmark of tumor cells. Metabolic changes in breast cancer cells make them more strictly dependent on EAAs, highlighting the potential of amino acid deprivation therapy.…”

“…Increasing dietary uptake of BCAAs can inhibit breast tumor growth in orthotopic xenotransplantation models and increase the activity of natural killer (NK) cells while inhibiting lung metastasis of breast cancer. Therefore, increasing BCAA uptake may be a practical dietary therapy for breast cancer 25 …”