SLC6A14 mediates Na(+)/Cl(-)-coupled concentrative uptake of a broad-spectrum of
amino acids. It is expressed at low levels in many tissues but up-regulated in certain
cancers. Pharmacological blockade of SLC6A14 causes
amino acid starvation in
estrogen receptor positive (ER+)
breast cancer cells and suppresses their proliferation in vitro and in vivo. In the present study, 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 (Polyoma middle T oncogene-transgenic mouse and mouse mammary tumour virus promoter-Neu-transgenic 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 major compensatory changes in the expression of other
amino acid transporter mRNAs. There was also no change in mammary gland development in the knockout mouse. However, when crossed with PyMT-Tg mice or MMTV/Neu (mouse mammary tumour virus promoter-Neu)-Tg mice, the development and progression of
breast cancer were markedly decreased on Slc6a14(-/-) background. Analysis of transcriptomes in tumour tissues from wild-type mice and Slc6a14-null mice indicated no compensatory changes in the expression of any other
amino acid transporter mRNA. However, the tumours from the null mice showed evidence of
amino acid starvation, decreased mTOR signalling and decreased cell proliferation. These studies demonstrate that SLC6A14 is critical for the maintenance of
amino acid nutrition and optimal
mammalian target of rapamycin (mTOR) signalling in ER+
breast cancer and that the transporter is a potential target for development of a novel class of anti-
cancer drugs targeting
amino acid nutrition in tumour cells.