PMID- 29363134
OWN - NLM
STAT- MEDLINE
DCOM- 20181211
LR  - 20181211
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 142
IP  - 12
DP  - 2018 Jun 15
TI  - The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through 
      distinct but overlapping mechanisms.
PG  - 2529-2542
LID - 10.1002/ijc.31276 [doi]
AB  - High metabolic and proliferative rates in cancer cells lead to production of 
      large amounts of H(+) and CO(2) , and as a result, net acid extruding 
      transporters are essential for the function and survival of cancer cells. We 
      assessed protein expression of the Na(+) /H(+) exchanger NHE1, the Na(+) - HCO3- 
      cotransporter NBCn1, and the lactate-H(+) cotransporters MCT1 and -4 by 
      immunohistochemical analysis of a large cohort of breast cancer samples. We found 
      robust expression of these transporters in 20, 10, 4 and 11% of samples, 
      respectively. NHE1 and NBCn1 expression both correlated positively with 
      progesterone receptor status, NHE1 correlated negatively and NBCn1 positively 
      with HER2 status, whereas MCT4 expression correlated with lymph node status. 
      Stable shRNA-mediated knockdown (KD) of either NHE1 or NBCn1 in the MDA-MB-231 
      triple-negative breast cancer (TNBC) cell line significantly reduced steady-state 
      intracellular pH (pH(i) ) and capacity for pH(i) recovery after an acid load. 
      Importantly, KD of any of the three transporters reduced in vivo primary tumor 
      growth of MDA-MB-231 xenografts. However, whereas KD of NBCn1 or MCT4 increased 
      tumor-free survival and decreased in vitro proliferation rate and colony growth 
      in soft agar, KD of NHE1 did not have these effects. Moreover, only MCT4 KD 
      reduced Akt kinase activity, PARP and CD147 expression and cell motility. This 
      work reveals that different types of net acid extruding transporters, NHE1, NBCn1 
      and MCT4, are frequently expressed in patient mammary tumor tissue and 
      demonstrates for the first time that they promote growth of TNBC human mammary 
      tumors in vivo via distinct but overlapping mechanisms.
CI  - (c) 2018 UICC.
FAU - Andersen, Anne Poder
AU  - Andersen AP
AD  - Section for Cell Biology and Physiology, Department of Biology, Faculty of 
      Science, University of Copenhagen, Copenhagen, Denmark.
FAU - Samsoe-Petersen, Jacob
AU  - Samsoe-Petersen J
AD  - Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical 
      Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Oernbo, Eva Kjer
AU  - Oernbo EK
AD  - Section for Cell Biology and Physiology, Department of Biology, Faculty of 
      Science, University of Copenhagen, Copenhagen, Denmark.
FAU - Boedtkjer, Ebbe
AU  - Boedtkjer E
AUID- ORCID: 0000-0002-5078-9279
AD  - Department of Biomedicine, Aarhus University, Aarhus, Denmark.
FAU - Moreira, Jose M A
AU  - Moreira JMA
AD  - Section for Molecular Disease Biology, Department of Drug Design and 
      Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 
      Copenhagen, Denmark.
FAU - Kveiborg, Marie
AU  - Kveiborg M
AD  - Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical 
      Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Pedersen, Stine Falsig
AU  - Pedersen SF
AUID- ORCID: 0000-0002-3044-7714
AD  - Section for Cell Biology and Physiology, Department of Biology, Faculty of 
      Science, University of Copenhagen, Copenhagen, Denmark.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180207
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Monocarboxylic Acid Transporters)
RN  - 0 (Muscle Proteins)
RN  - 0 (SLC16A4 protein, human)
RN  - 0 (SLC4A7 protein, human)
RN  - 0 (SLC9A1 protein, human)
RN  - 0 (Sodium-Bicarbonate Symporters)
RN  - 0 (Sodium-Hydrogen Exchanger 1)
SB  - IM
MH  - Animals
MH  - Biomarkers, Tumor/*analysis
MH  - Breast Neoplasms/metabolism/mortality/*pathology
MH  - Disease-Free Survival
MH  - Female
MH  - Heterografts
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Mice
MH  - Monocarboxylic Acid Transporters/*metabolism
MH  - Muscle Proteins/*metabolism
MH  - Sodium-Bicarbonate Symporters/*metabolism
MH  - Sodium-Hydrogen Exchanger 1/*metabolism
OTO - NOTNLM
OT  - MCT4
OT  - NBCn1
OT  - NHE1
OT  - acid-base transport
OT  - breast cancer
EDAT- 2018/01/25 06:00
MHDA- 2018/12/12 06:00
CRDT- 2018/01/25 06:00
PHST- 2017/09/01 00:00 [received]
PHST- 2017/12/16 00:00 [revised]
PHST- 2018/01/17 00:00 [accepted]
PHST- 2018/01/25 06:00 [pubmed]
PHST- 2018/12/12 06:00 [medline]
PHST- 2018/01/25 06:00 [entrez]
AID - 10.1002/ijc.31276 [doi]
PST - ppublish
SO  - Int J Cancer. 2018 Jun 15;142(12):2529-2542. doi: 10.1002/ijc.31276. Epub 2018 
      Feb 7.