Abstract
Understanding the consequences of miR-145 reintroduction in human breast cancer (BC) could reveal its tumor-suppressive functions and may disclose new aspects of BC biology. Therefore, we characterized the effects of miR-145 re-expression in BC cell lines by using proliferation and apoptosis assays. As a result, we found that miR-145 exhibited a pro-apoptotic effect, which is dependent on TP53 activation, and that TP53 activation can, in turn, stimulate miR-145 expression, thus establishing a death-promoting loop between miR-145 and TP53. We also found that miR-145 can downregulate estrogen receptor-α (ER-α) protein expression through direct interaction with two complementary sites within its coding sequence. In conclusion, we described a tumor suppression function of miR-145 in BC cell lines, and we linked miR-145 to TP53 and ER-α. Moreover, our findings support a view that miR-145 re-expression therapy could be mainly envisioned in the specific group of patients with ER-α-positive and/or TP53 wild-type tumors.
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Accession codes
Abbreviations
- miRNA:
-
microRNA
- mRNA:
-
messenger RNA
- 3′UTR:
-
3′ untranslated region
- BC:
-
breast cancer
- ER-α:
-
estrogen receptor-α
- PCR:
-
polymerase chain reaction
- wt:
-
wild-type
- PI:
-
propidium iodide
- PARP:
-
poly(ADP-ribose) polymerase
- PUMA:
-
p53 upregulated modulator of apoptosis
- CDKN1A:
-
cyclin-dependent kinase inhibitor 1A
- siRNA:
-
small interfering RNA
- ESR1:
-
estrogen receptor 1
- CDS:
-
coding sequence
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Acknowledgements
We thank Izabela Fokt (MD Anderson Cancer Center) for Adriamycin synthesis, Deepa Sampath (MD Anderson Cancer Center) for PUMA antibody and the Powis laboratory for the use of a luciferase plate reader. We thank Donald Norwood from the MD Anderson Scientific Publication Department for editing the paper. GAC is supported by The University of Texas MD Anderson Cancer Center Research Trust, The University of Texas System Regents Research Scholar Award and the Ladjevardian Regents Research Scholar Fund. This study was funded also by an Institutional Research Grant and the National Institutes of Health Cancer Center Support (Core) Grant (New Faculty Award) to GAC, and by the Associazione Italiana per la Ricerca sul Cancro and Fondazione Cariplo Progetto NOBEL (to MN).
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Spizzo, R., Nicoloso, M., Lupini, L. et al. miR-145 participates with TP53 in a death-promoting regulatory loop and targets estrogen receptor-α in human breast cancer cells. Cell Death Differ 17, 246–254 (2010). https://doi.org/10.1038/cdd.2009.117
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DOI: https://doi.org/10.1038/cdd.2009.117
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