Molecular Dependence of Estrogen Receptor–Negative Breast Cancer on a Notch-Survivin Signaling Axis
- 1 July 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (13), 5273-5281
- https://doi.org/10.1158/0008-5472.can-07-6673
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 γ-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. [Cancer Res 2008;68(13):5273–81]Keywords
This publication has 50 references indexed in Scilit:
- Compartmentalized Phosphorylation of IAP by Protein Kinase A Regulates CytoprotectionMolecular Cell, 2007
- Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care?Nature Reviews Cancer, 2007
- Hypoxia-Inducible Factors, Stem Cells, and CancerCell, 2007
- Epidermal growth factor receptor mutations in lung cancerNature Reviews Cancer, 2007
- A collection of breast cancer cell lines for the study of functionally distinct cancer subtypesCancer Cell, 2006
- Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the familyEMBO Reports, 2006
- Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapyNature Clinical Practice Oncology, 2006
- A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast CancerNew England Journal of Medicine, 2004
- Validating survivin as a cancer therapeutic targetNature Reviews Cancer, 2003
- Gene expression profiling predicts clinical outcome of breast cancerNature, 2002