Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Abstract

Please cite this article as: Amith Schammim Ray, Fliegel Larry.Na+/H+ exchangermediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics.Seminars in Cancer Biology http://dx.doi. org/10.1016/j.semcancer.2017.01.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abstract (250 words):Breast cancer is the leading cause of cancer-related death in women in Europe and North America, and metastasis is the primary cause of fatality in patients with breast cancer. While some breast cancers are quite treatable, the triple-negative breast cancers are more metastatic and resistant to chemotherapy. There is clearly an urgent need for better treatments for this form of the disease. Breast cancer is characterized by genetically complex intra-tumour heterogeneity, particularly within the triple-negative clinical subtype. This complicates treatment options, so the development of specifically targeted chemotherapy for less treatable forms is critical.Dysregulation of pH homeostasis is a common factor in breast tumour cells. This occurs in concert with a metabolic switch to aerobic glycolysis that occurs at the onset of oncogenic transformation. The Na + /H + exchanger isoform 1 (NHE1) is the major pH regulatory protein involved in the increased proton extrusion of breast cancer cells. Its increased activity results in intracellular alkalinisation and extracellular acidification that drives cancer progression. The acidification of the extracellular tumour microenvironment also contributes to the development of chemotherapy resistance. In this review, we outline the role of H + as a carcinogenic signal and the role and regulation of NHE1 as a trigger for metastasis. We review recent evidence supporting the use of pharmacological inhibitors of NHE1 as a viable treatment option for triplenegative breast cancer.

Functionally Coherent Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling

“…The SLC9A6 Na + /H + antiporter was found in NetNC-FTI ion transport clusters for sna_2-4h_Toll 10b and twi_2-4h_Toll 10b . Alterations in pH by Na + /H + exchangers, particularly SLC9A1, drive basal-like breast cancer progression and chemoresistance (Amith and Fliegel, 2017). SLC9A6 was 1.6-fold upregulated in basal-like relative to normal-like tumours (p<8.4x10 -71 ) and might drive pH dysregulation as part of an EMT-like programme in basal-like cancers.…”

Amino Acids 563–566 of the Na+/H+ Exchanger Isoform 1 C-Terminal Cytosolic Tail Prevent Protein Degradation and Stabilize Protein Expression and Activity

“…In human pathology, NHE1 is critical in several diseases, including myocardial heart hypertrophy and ischemia reperfusion damage [7]. NHE1 is also important in breast cancer, where it acts as a trigger for metastasis [8,9]. NHE1 consists of two domains: a membrane domain that transports ions and a C-terminal cytosolic regulatory domain.…”

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

“…d) pH, proton transporters (PTs), proton pumps (PPs) and their inhibitors (PTIs and PPIs) [14,32,36,38,[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. e) pH and voltage gated sodium channels (VGSC) [56][57][58][59][60][61].…”