Deletion of the amino acid transporter SLC6A14 suppresses tumour growth in spontaneous mouse models of breast cancer

Ellappan Babu, Yangzom D. Bhutia, Sabarish Ramachandran, Jaya Pranava Gnana-Prakasam, Puttur D Prasad, Muthusamy Thangaraju, Vadivel Ganapathy

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17-23
Number of pages7
JournalBiochemical Journal
Volume469
Issue number1
DOIs
StatePublished - Jul 1 2015

Fingerprint

Amino Acid Transport Systems
Tumors
Breast Neoplasms
Amino Acids
Growth
Knockout Mice
Mouse mammary tumor virus
Neoplasms
Sirolimus
Nutrition
Starvation
Viruses
Carcinogens
Transgenic Mice
Cells
Tissue
Messenger RNA
Cell proliferation
Gene Expression Profiling
Drug Delivery Systems

Keywords

  • Amino acid transport
  • Breast cancer
  • Mechanistic target of rapamycin (mTOR)
  • Nutrient signalling
  • Slc6a14-null mouse

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Deletion of the amino acid transporter SLC6A14 suppresses tumour growth in spontaneous mouse models of breast cancer. / Babu, Ellappan; Bhutia, Yangzom D.; Ramachandran, Sabarish; Gnana-Prakasam, Jaya Pranava; Prasad, Puttur D; Thangaraju, Muthusamy; Ganapathy, Vadivel.

In: Biochemical Journal, Vol. 469, No. 1, 01.07.2015, p. 17-23.

Research output: Contribution to journalArticle

Babu, Ellappan ; Bhutia, Yangzom D. ; Ramachandran, Sabarish ; Gnana-Prakasam, Jaya Pranava ; Prasad, Puttur D ; Thangaraju, Muthusamy ; Ganapathy, Vadivel. / Deletion of the amino acid transporter SLC6A14 suppresses tumour growth in spontaneous mouse models of breast cancer. In: Biochemical Journal. 2015 ; Vol. 469, No. 1. pp. 17-23.
@article{5761b1d7f54f41bea10c486a52407c0d,
title = "Deletion of the amino acid transporter SLC6A14 suppresses tumour growth in spontaneous mouse models of breast cancer",
abstract = "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.",
keywords = "Amino acid transport, Breast cancer, Mechanistic target of rapamycin (mTOR), Nutrient signalling, Slc6a14-null mouse",
author = "Ellappan Babu and Bhutia, {Yangzom D.} and Sabarish Ramachandran and Gnana-Prakasam, {Jaya Pranava} and Prasad, {Puttur D} and Muthusamy Thangaraju and Vadivel Ganapathy",
year = "2015",
month = "7",
day = "1",
doi = "10.1042/BJ20150437",
language = "English (US)",
volume = "469",
pages = "17--23",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "1",

}

TY - JOUR

T1 - Deletion of the amino acid transporter SLC6A14 suppresses tumour growth in spontaneous mouse models of breast cancer

AU - Babu, Ellappan

AU - Bhutia, Yangzom D.

AU - Ramachandran, Sabarish

AU - Gnana-Prakasam, Jaya Pranava

AU - Prasad, Puttur D

AU - Thangaraju, Muthusamy

AU - Ganapathy, Vadivel

PY - 2015/7/1

Y1 - 2015/7/1

N2 - 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.

AB - 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.

KW - Amino acid transport

KW - Breast cancer

KW - Mechanistic target of rapamycin (mTOR)

KW - Nutrient signalling

KW - Slc6a14-null mouse

UR - http://www.scopus.com/inward/record.url?scp=84935435481&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84935435481&partnerID=8YFLogxK

U2 - 10.1042/BJ20150437

DO - 10.1042/BJ20150437

M3 - Article

C2 - 26173258

AN - SCOPUS:84935435481

VL - 469

SP - 17

EP - 23

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 1

ER -