Everolimus Reverses Palbociclib Resistance in ER+ Human Breast Cancer Cells by Inhibiting Phosphatidylinositol 3-Kinase(PI3K)/Akt/Mammalian Target of Rapamycin (mTOR) Pathway.

Content Provider	Europe PMC
Author	Chen, Lin Yang, Guangsheng Dong, Hongming
Copyright Year	2019
Abstract	BackgroundPalbociclib, a specific inhibitor of CDK4/6, has been shown to provide a survival benefit in hormone receptor-positive advanced breast cancer; however, its resistance and related mechanisms are unclear.Material/MethodsIn this study, we constructed palbociclib-resistant hormone receptor-positive breast cancer cells (MCF-7-P) via culturing with palbociclib for at least 6 months. Quantitative real-time PCR (qRT-PCR) and western blot were used to detect the expression of stemness markers in MCF-7-P and MCF-7 cells. Additionally, cell spheroid formation, Transwell migration, ALDH1 activity, and flow cytometry assays were performed to detect stemness and migration ability of MCF-7-P cells, and the effects of everolimus on MCF-7-P cells stemness and migration ability. Growth inhibition assay was used to examine the effect of everolimus on the sensitivity of palbociclib in MCF-7-P and MCF-7 cells.ResultsMCF-7-P cells had stronger stemness and higher expression of ABCG2 and MDR1. Moreover, PI3K/Akt/mTOR signaling was hyper-activated in MCF-7-P cells. Additionally, everolimus, which is a mTOR inhibitor, attenuated MCF-7-P cells stemness and re-sensitized MCF-7-P cells to palbociclib. Importantly, everolimus enhanced the antitumor effect of palbociclib in palbociclib-sensitive hormone receptor-positive cells (MCF-7 cells).ConclusionsThese findings provide a rationale for future clinical trials of palbociclib and everolimus combination-based therapy in hormone receptor-positive breast cancer.
ISSN	12341010
Journal	Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
Volume Number	25
PubMed Central reference number	PMC6327776
PubMed reference number	30605443
e-ISSN	16433750
DOI	10.12659/msm.912929
Language	English
Publisher	International Scientific Literature, Inc.
Publisher Date	2019-01-03
Access Restriction	Open
Rights License	This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) © Med Sci Monit, 2019
Subject Keyword	Breast Neoplasms, Male Drug Resistance Stem Cell Research TOR Serine-Threonine Kinases
Content Type	Text
Resource Type	Article
Subject	Medicine