Publications

@article{Mahmoud2022-ls,

title = {Challenges for Triple Negative Breast Cancer treatment: 

 Defeating heterogeneity and cancer stemness},

author = {Rinad Mahmoud and Paloma Ord\'{o}\~{n}ez-Mor\'{a}n and Cinzia Allegrucci},

year  = {2022},

date = {2022-09-01},

journal = {Cancers (Basel)},

volume = {14},

number = {17},

pages = {4280},

publisher = {MDPI AG},

abstract = {The Triple Negative Breast Cancer (TNBC) subtype is known to 

 have a more aggressive clinical course compared to other breast 

 cancer subtypes. Targeted therapies for this type of breast 

 cancer are limited and patients are mostly treated with 

 conventional chemo- and radio-therapies which are not specific 

 and do not target resistant cells. Therefore, one of the major 

 clinical challenges is to find compounds that target the 

 drug-resistant cell populations which are responsible for 

 reforming secondary tumours. The molecular profiling of the 

 different TNBC subtypes holds a promise for better defining 

 these resistant cells specific to each tumour. To this end, a 

 better understanding of TNBC heterogeneity and cancer stemness 

 is required, and extensive genomic analysis can help to 

 understand the disease complexity and distinguish new molecular 

 drivers that can be targeted in the clinics. The use of 

 persister cancer cell-targeting therapies combined with other 

 therapies may provide a big advance to improve TNBC patients' 

 survival.},

keywords = {Differentiation, drug resistance, persister cells, phenotype, stemness, triple negative breast cancer, tumour heterogeneity},

pubstate = {published},

tppubtype = {article}

}

@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}

}