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.
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).


OBJECTIVE
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.
IVIC, Tumor Cell Biology Laboratory, Center for Microbiology & Cell Biology Apartado 21827, Caracas 1020 A, Venezuela. Electronic address: manuel.rieber@gmail.com.
Manuel
M
Rieber
IVIC, Tumor Cell Biology Laboratory, Center for Microbiology & Cell Biology Apartado 21827, Caracas 1020 A, Venezuela. Electronic address: mary.rieber@gmail.com.
Mary
M
Strasberg-Rieber
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D005260:Female; D016158:Genes, p53 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D061986:MCF-7 Cells; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology* / Q000627:therapeutic use
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates; C017092:bromopyruvate
3-Bromopyruvate; Epithelial–mesenchymal transition; Estrogen hypersensitivity; MEK inhibition