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Molecular dependence of estrogen receptor-negative breast cancer on a notch-survivin signaling axis.

Authors :
Lee CW
Raskett CM
Prudovsky I
Altieri DC
Source :
Cancer research [Cancer Res] 2008 Jul 01; Vol. 68 (13), pp. 5273-81.
Publication Year :
2008

Abstract

Despite progress in the management of breast cancer, the molecular underpinnings of clinically aggressive subtypes of the disease are not well-understood. Here, we show that activation of Notch developmental signaling in estrogen receptor (ER)-negative breast cancer cells results in direct transcriptional up-regulation of the apoptosis inhibitor and cell cycle regulator survivin. This response is associated with increased expression of survivin at mitosis, enhanced cell proliferation, and heightened viability at cell division. Conversely, targeting Notch signaling with a peptidyl gamma-secretase inhibitor suppressed survivin levels, induced apoptosis, abolished colony formation in soft agar, and inhibited localized and metastatic tumor growth in mice, without organ or systemic toxicity. In contrast, ER+ breast cancer cells, or various normal cell types, were insensitive to Notch stimulation. Therefore, ER- breast cancer cells become dependent on Notch-survivin signaling for their maintenance, in vivo. Therapeutic targeting of this pathway may be explored for individualized treatment of patients with clinically aggressive, ER- breast cancer.

Details

Language :
English
ISSN :
1538-7445
Volume :
68
Issue :
13
Database :
MEDLINE
Journal :
Cancer research
Publication Type :
Academic Journal
Accession number :
18593928
Full Text :
https://doi.org/10.1158/0008-5472.CAN-07-6673