Journal
BIOCHEMICAL PHARMACOLOGY
Volume 88, Issue 2, Pages 169-177Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2014.01.025
Keywords
Epithelial-mesenchymal transition; Estrogen hypersensitivity; MEK inhibition; 3-Bromopyruvate
Categories
Funding
- Ministerio de Ciencia y Tecnologia (Fonacit-Mision Ciencia subproyecto SPNS 4-Cancer)
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Background: Most breast cancers express the estrogen receptor alpha (ER alpha(+)), harbor wt TP53, depend on estrogen/ERK signalling for proliferation, and respond to anti-estrogens. However, concomittant activation of the epidermal growth factor receptor (EGFR)/MEK pathway promotes resistance by decreasing estrogen dependence. Previously, we showed that retroviral transduction of mutant p53 R175H into wt TP53 ER alpha(+) MCF-7 cells induces epidermal growth factor (EGF)-independent proliferation, activation of the EGF receptor (p-EGFR) and some characteristics of epithelial-mesenchymal transition (EMT). Purpose: To investigate whether p53 inactivation augments ER alpha(+) cell proliferation in response to restrictive estradiol, chemical MEK inhibition or metabolic inhibitors. Results: Introduction of mutant p53 R175H lowered expression of p53-dependent PUMA and p21WAF1, decreased E-cadherin and cytokeratin 18 associated with EMT, but increased the % of proliferating ER alpha(+)/Ki67 cells, diminishing estrogen dependence. These cells also exhibited higher proliferation in the presence of MEK-inhibitor UO126, reciprocally correlating with preferential susceptibility to the pyruvate analog 3-bromopyruvate (3-BrPA) without a comparable response to 2-deoxyglucose. p53 siRNA silencing by electroporation in wt TP53 MCF-7 cells also decreased estrogen dependence and response to MEK inhibition, while also conferring susceptibility to 3-BrPA. Conclusions: (a) ER alpha(+) breast cancer cells dysfunctional for TP53 which proliferate irrespective of low estrogen and chemical MEK inhibition are likely to increase metabolic consumption becoming increasingly susceptible to 3-BrPA; (b) targeting the pyruvate pathway may improve response to endocrine therapy in ER alpha(+) breast cancer With p53 dysfunction. (C) 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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