The transcobalamin receptor, CD320, is a therapeutic target for metastatic triple negative breast cancer

Vitamin B12 is an essential micronutrient that functions as a cofactor for enzymes in the folate and propionate metabolism pathways, placing it at the center of nucleotide metabolism, redox balance, and cell fate decisions. Following dietary intake of vitamin B12, vitamin B12 binds to transcobalamin (TC), which protects it from degradation. Cellular uptake of vitamin B12 is mediated by the TC receptor, CD320, positioning CD320 in a prime position to regulate vitamin B12 availability and govern cell fate decisions. Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited treatment options and poor survival rates once metastasis to distant sites occurs, highlighting the need for novel therapeutic strategies for metastatic TNBC. Using publicly available datasets, we found that CD320 was highly expressed in TNBC cell lines and patient samples compared to hormone receptor-positive and HER2-positive subtypes. High expression of CD320 was associated with poor prognosis specifically in TNBC, unlike in other subtypes. Metastasis accounts for the majority of breast cancer-related deaths, and progression into metastatic disease requires cancer cells to adapt to the different pressures throughout the metastatic cascade. Thus, we hypothesized that upregulation of CD320 represents a metabolic adaptation of TNBC metastasis to meet the steep vitamin B12 demand that drives this aggressive phenotype. Consistent with this hypothesis, we observed that CD320 expression was significantly higher in TNBC metastases compared to the expression in primary tumors. Strikingly, suppression of CD320 induced TNBC cell death while having no cytotoxic effect on mammary epithelial cells and markedly impaired metastatic progression in vivo , as demonstrated in orthotopic and experimental models of metastasis. Conversely, overexpression of CD320 in transformed mammary epithelial cells conferred aggressive properties, such as increased proliferation, suggesting that CD320 is not only required for TNBC metastasis but also sufficient to enable TNBC aggressiveness. Together, these findings establish CD320 as a critical regulator of TNBC growth and metastasis and reveal CD320 as a promising therapeutic target to selectively eliminate TNBC cells without eliminating the normal tissue counterpart.