BCATc modulates crosstalk between the PI3K/Akt and the Ras/ERK pathway regulating proliferation in triple negative breast cancer
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Mai Ahmed Shafei1, Thomas Forshaw1, Jasmine Davis1, Arwa Flemban1, David Qualtrough1, Sarah Dean1, Claire Perks2, Ming Dong3, Robert Newman4 and Myra Elizabeth Conway1
1 Faculty of Health and Applied Sciences, University of the West of England, Coldharbor Lane, Bristol, UK
2 IGFs and Metabolic Endocrinology Group, University of Bristol, Bristol Medical School, Bristol, UK
3 Department of Chemistry, North Carolina Agricultural and Technical State University, Greensboro, NC, USA
4 Department of Biology, North Carolina Agricultural and Technical State University, Greensboro, NC, USA
|Myra Elizabeth Conway,||email:||firstname.lastname@example.org|
Keywords: BCAT; PI3K-AKT; ERK; breast cancer
Received: February 10, 2020 Accepted: April 14, 2020 Published: May 26, 2020
The cytosolic branched chain aminotransferase (BCATc) protein has been found to be highly expressed in breast cancer subtypes, including triple negative breast cancer (TNBC), compared with normal breast tissue. The catabolism of branched-chain amino acids (BCAAs) by BCATc leads to the production of glutamate and key metabolites which further drive the TCA cycle, important for cellular metabolism and growth. Upregulation of BCATc has been associated with increased cell proliferation, cell cycle progression and metastasis in several malignancies including breast, gliomas, ovarian and colorectal cancer but the underlying mechanisms are unclear. As nutrient levels of BCAAs, substrates of BCATc, regulate the PI3K/Akt pathway we hypothesized that increased expression of BCATc would contribute to tumour cell growth through upregulation of the insulin/IGF-1 signalling pathway. This pathway is known to potentiate proliferation and metastasis of malignant cells through the activation of PI3K/Akt and the RAS/ERK signalling cascades. Here we show that knockdown of BCATc significantly reduced insulin and IGF-1-mediated proliferation, migration and invasion of TNBC cells. An analysis of this pathway showed that when overexpressed BCATc regulates proliferation through the PI3K/Akt axis, whilst simultaneously attenuating the Ras/Erk pathway indicating that BCATc acts as a conduit between these two pathways. This ultimately led to an increase in FOXO3a, a key regulator of cell proliferation and Nrf2, which mediates redox homeostasis. Together this data indicates that BCATc regulates TNBC cell proliferation, migration and invasion through the IGF-1/insulin PI3K/Akt pathway, culminating in the upregulation of FOXO3a and Nrf2, pointing to a novel therapeutic target for breast cancer treatment.
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