Deletion of the amino acid transporter Slc6a14 suppresses tumor growth in spontaneous mouse models of breast cancer
SLC6A14 mediates Na + /Cl --coupled concentrative uptake of a broad-spectrum of amino acids. It is expressed at low levels in many tissues but upregulated in certain cancers. Pharmacologic blockade of SLC6A14 causes amino acid starvation in ER+ breast cancer cells and suppresses their proliferation in vitro and in vivo. Here we interrogated the role of this transporter in breast cancer by deleting Slc6a14 in mice and monitoring the consequences of this deletion in models of spontaneous breast cancer (PyMT oncogene-Tg mouse and MMTV/Neu-Tg mouse). Slc6a14-knockout mice are viable, fertile, and phenotypically normal. The plasma amino acids were similar in wild type and knockout mice, and there were no compensatory changes in the expression of other amino acid transporters. There was also no change in mammary gland development in the knockout mouse. However, when crossed with PyMT-Tg mice orMMTV/Neu-Tg mice, the development and progression of breast cancer were markedly decreased on Slc6a14 -/- background. Analysis of transcriptomes in tumor tissues from wild type mice and Slc6a14-null mice indicated no compensatory changes in the expression of any other amino acid transporter. However, the tumors from the null mice showed evidence of amino acid starvation, decreased mTOR signaling, and decreased cell proliferation. These studies demonstrate that SLC6A14 is critical for the maintenance of amino acid nutrition and optimal mTOR signaling in ER+ breast cancer and that the transporter is a potential target for development of a novel class of anticancer drugs targeting amino acid nutrition in tumor cells.
Babu E; Bhutia Y; Ramachandran S; Gnana-Prakasam J; Prasad P; Thangaraju M; Ganapathy V
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