Regulation of low-density lipoprotein receptor expression in triple negative breast cancer by EGFR-MAPK signaling

Expression of the low-density lipoprotein receptor (LDLR) has been shown to play a critical role in hypercholesterolemia-associated breast cancer growth and is associated with shorter recurrence-free survival in human breast cancer studies. We sought to identify how circulating LDL cholesterol and t...

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Bibliographic Details
Published in:Scientific reports 2021-09, Vol.11 (1), p.17927-17927, Article 17927
Main Authors: Scully, Tiffany, Kase, Nathan, Gallagher, Emily J., LeRoith, Derek
Format: Article
Language:English
Subjects:
631/67/1347
631/80/86/2368
Breast cancer
Cholesterol
Epidermal growth factor
Epidermal growth factor receptors
Humanities and Social Sciences
Hypercholesterolemia
LDLR protein
Low density lipoprotein
Low density lipoprotein receptors
MAP kinase
multidisciplinary
Phosphorylation
Receptor density
Science
Science (multidisciplinary)
Signal transduction
Transcription
Tumor cell lines
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Summary:Expression of the low-density lipoprotein receptor (LDLR) has been shown to play a critical role in hypercholesterolemia-associated breast cancer growth and is associated with shorter recurrence-free survival in human breast cancer studies. We sought to identify how circulating LDL cholesterol and tumor LDLR might accelerate oncogenic processes by determining whether increased LDLR expression and cholesterol uptake are associated with the activation of the epidermal growth factor receptor (EGFR) signaling pathway in triple negative breast cancer (TNBC) cell lines. EGF stimulation of MDA-MB-468 (MDA468) cells activated p44/42MAPK (MAPK), increased expression of LDLR, and fluorescent LDL cholesterol uptake. However, stimulation of MDA-MB-231 (MDA231) cells with EGF did not lead to increased expression of LDLR despite inducing phosphorylation of EGFR. Inhibition of MAPK using UO126 in MDA231 cells reduced LDLR expression, and in MDA468 cells, UO126 impaired the LDLR increase in response to EGF. MDA468 cells exposed to the transcription inhibitor, Actinomycin, prior to treatment with EGF showed reduced degradation of LDLR mRNA compared to vehicle-treated cells. Our results suggest that the EGF-associated increase in LDLR protein expression is cell line-specific. The common pathway regulating LDLR expression was MAPK in both TNBC cell lines.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-97327-y