p53 inactivation decreases dependence on estrogen/ERK signalling for proliferation but promotes EMT and susceptility to 3-bromopyruvate in ERα+ breast cancer MCF-7 cells
| Autor: | Mary Strasberg-Rieber, Manuel Rieber |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty Epithelial-Mesenchymal Transition MAP Kinase Signaling System medicine.drug_class Breast Neoplasms Pyruvate Dehydrogenase Complex Biochemistry Epidermal growth factor Internal medicine medicine Humans Epidermal growth factor receptor Epithelial–mesenchymal transition Pyruvates Estrogen receptor beta Cell Proliferation 3-Bromopyruvate Pharmacology biology Estrogen Receptor alpha Genes p53 Endocrinology MCF-7 Estrogen MEK inhibition MCF-7 Cells Cancer research biology.protein Estrogen hypersensitivity Female Estrogen receptor alpha |
| Zdroj: | Biochemical Pharmacology. 88(2):169-177 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2014.01.025 |
| Popis: | Background Most breast cancers express the estrogen receptor alpha (ERα + ), 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 ERα + 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 ERα + 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 ERα + /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) ERα + 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 ERα + breast cancer with p53 dysfunction. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect