Publications

@article{Carroll2022-fd,

title = {Targeting hypoxia regulated sodium driven bicarbonate 

 transporters reduces triple negative breast cancer metastasis},

author = {Christopher Paul Carroll and Hannah Bolland and Eric Vancauwenberghe and Pamela Collier and Alison A Ritchie and Philip A Clarke and Anna M Grabowska and Adrian L Harris and Alan McIntyre},

year  = {2022},

date = {2022-03-01},

journal = {Neoplasia},

volume = {25},

pages = {41\textendash52},

publisher = {Elsevier BV},

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.},

keywords = {EMT, Hypoxia, Metastasis, NDBT, triple negative breast cancer, Tumour Acidosis},

pubstate = {published},

tppubtype = {article}

}