» Articles » PMID: 35150959

Targeting Hypoxia Regulated Sodium Driven Bicarbonate Transporters Reduces Triple Negative Breast Cancer Metastasis

Overview
Journal Neoplasia
Publisher Elsevier
Specialty Oncology
Date 2022 Feb 12
PMID 35150959
Authors
Affiliations
Soon will be listed here.
Abstract

Regions of low oxygen (hypoxia) are found in >50% of breast tumours, most frequently in the more aggressive triple negative breast cancer subtype (TNBC). Metastasis is the cause of 90% of breast cancer patient deaths. Regions of tumour hypoxia tend to be more acidic and both hypoxia and acidosis increase tumour metastasis. In line with this the metastatic process is dependent on pH regulatory mechanisms. We and others have previously identified increased hypoxic expression of Na driven bicarbonate transporters (NDBTs) as a major mechanism of tumour pH regulation. Hypoxia induced the expression of NDBTs in TNBC, most frequently SLC4A4 and SLC4A5. NDBT inhibition (S0859) and shRNA knockdown suppressed migration (40% reduction) and invasion (70% reduction) in vitro. Tumour xenograft metastasis in vivo was significantly reduced by NDBT knockdown. To investigate the mechanism by which NDBTs support metastasis, we investigated their role in regulation of phospho-signalling, epithelial-to-mesenchymal transition (EMT) and metabolism. NDBT knockdown resulted in an attenuation in hypoxic phospho-signalling activation; most notably LYN (Y397) reduced by 75%, and LCK (Y394) by 72%. The metastatic process is associated with EMT. We showed that NDBT knockdown inhibited EMT, modulating the expression of key EMT transcription factors and ablating the expression of vimentin whilst increasing the expression of E-cadherin. NDBT knockdown also altered metabolic activity reducing overall ATP and extracellular lactate levels. These results demonstrate that targeting hypoxia-induced NDBT can be used as an approach to modulate phospho-signalling, EMT, and metabolic activity and reduce tumour migration, invasion, and metastasis in vivo.

Citing Articles

Carbonic Anhydrase IX Enzyme in Triple Negative Breast Carcinoma: Relationship With Prognostic Factors and Response to Neoadjuvant Chemotherapy.

Arslan Solmaz O, Kutluer N, Bozan M Eur J Breast Health. 2025; 21(1):57-62.

PMID: 39744916 PMC: 11706115. DOI: 10.4274/ejbh.galenos.2024.2024-6-1.


Single-nucleus RNA-seq dissection of choroid plexus tumor cell heterogeneity.

Hill A, Okonechnikov K, Herr M, Thomas C, Thongjuea S, Hasselblatt M EMBO J. 2024; 43(24):6766-6791.

PMID: 39482394 PMC: 11649822. DOI: 10.1038/s44318-024-00283-2.


Hypoxia-induced epigenetic regulation of breast cancer progression and the tumour microenvironment.

Capatina A, Malcolm J, Stenning J, Moore R, Bridge K, Brackenbury W Front Cell Dev Biol. 2024; 12:1421629.

PMID: 39282472 PMC: 11392762. DOI: 10.3389/fcell.2024.1421629.


Targeting Pivotal Hallmarks of Cancer for Enhanced Therapeutic Strategies in Triple-Negative Breast Cancer Treatment-In Vitro, In Vivo and Clinical Trials Literature Review.

Szulc A, Wozniak M Cancers (Basel). 2024; 16(8).

PMID: 38672570 PMC: 11047913. DOI: 10.3390/cancers16081483.


Acid-base transporters in the context of tumor heterogeneity.

Pedersen S Pflugers Arch. 2024; 476(4):689-701.

PMID: 38332178 DOI: 10.1007/s00424-024-02918-z.


References
1.
McIntyre A, Hulikova A, Ledaki I, Snell C, Singleton D, Steers G . Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth. Cancer Res. 2016; 76(13):3744-55. DOI: 10.1158/0008-5472.CAN-15-1862. View

2.
Viklund J, Avnet S, De Milito A . Pathobiology and Therapeutic Implications of Tumor Acidosis. Curr Med Chem. 2016; 24(26):2827-2845. DOI: 10.2174/0929867323666161228142849. View

3.
Groger N, Vitzthum H, Frohlich H, Kruger M, Ehmke H, Braun T . Targeted mutation of SLC4A5 induces arterial hypertension and renal metabolic acidosis. Hum Mol Genet. 2011; 21(5):1025-36. DOI: 10.1093/hmg/ddr533. View

4.
Svastova E, Witarski W, Csaderova L, Kosik I, Skvarkova L, Hulikova A . Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J Biol Chem. 2011; 287(5):3392-402. PMC: 3270993. DOI: 10.1074/jbc.M111.286062. View

5.
Benej M, Pastorekova S, Pastorek J . Carbonic anhydrase IX: regulation and role in cancer. Subcell Biochem. 2013; 75:199-219. DOI: 10.1007/978-94-007-7359-2_11. View