Abstract 3928: Genetic deletion or pharmacologic blockade of the amino acid transporter Slc6a14 in mice suppresses breast cancer induced by Polyoma middle T oncogene

Tumor cells have an increased need for amino acids. Mammalian cells cannot synthesize essential amino acids; they must obtain these amino acids via specific transporters. Glutamine, though a non-essential amino acid, is critical for tumor cells (glutamine addiction). Entry of amino acids into tumor cells is enhanced by upregulation of specific transporters. If we can interfere with the entry of amino acids into tumor cells, we should be able to starve these cells to death. If the transporters that are specifically induced in tumor cells are identified, blockade of the induced transporters would constitute a logical strategy for cancer treatment. Mammalian cells express ∼40 amino acid transporters, expressed in different combinations and in a cell type-specific manner. Among them, SLC6A14 is unique in that it transports all essential amino acids as well as glutamine, and is expressed only at low levels in normal tissues, but induced in colon cancer and in ER+ breast cancer. Tumor cells in these cancers upregulate SLC6A14 to meet their increased demand for essential amino acids and glutamine, indicating that SLC6A14 drives their “glutamine addiction.” We have now established the potential of this transporter as a drug target for breast cancer treatment using genetic and pharmacologic approaches. For this, we first generated Slc6a14 -/- mouse. The Slc6a14 gene is located on X chromosome. Deletion of the gene is not lethal and there is no overt phenotype in hemizygous males (-/y) or in homozygous females (-/-). We then examined the progression of breast cancer in Polyoma middle T antigen (Py-MT) Tg mouse on Slc6a14 +/+ and Slc6a14 -/- background. Deletion of Slc6a14 markedly suppressed breast cancer and lung metastasis induced by the Py-MT oncogene. We have also identified -methyl-L-tryptophan (-MLT) as a selective blocker of Slc6a14. We investigated the consequences of pharmacologic blockade of Slc6a14 on Py-MT-induced breast cancer with oral administration of -MLT (1 mg/ml in drinking water). The blocker was able to suppress breast cancer to a marked extent. Py-MT-induced breast tumors showed robust upregulation of Slc6a14; however, the tumors also showed upregulation of Slc7a5/Slc3a2, another amino acid transporter. Therefore, we examined the interaction of -MLT with Slc7a5/Slc3a2 and found that while -MLT is a blocker of Slc6a14, it is a transportable substrate for Slc7a5/Slc3a2, demonstrating that only the function of Slc6a14 is selectively blocked by -MLT. We conclude that blockade of Slc6a14 is a viable strategy for treatment of certain specific subtypes of breast cancer (e.g., ER-positive) that are associated with upregulation of the transporter. Citation Format: Babu Ellappan, Yangzom D. Bhutia, Muthusamy Thangaraju, Puttur D. Prasad, Vadivel Ganapathy. Genetic deletion or pharmacologic blockade of the amino acid transporter Slc6a14 in mice suppresses breast cancer induced by Polyoma middle T oncogene. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3928. doi:10.1158/1538-7445.AM2014-3928