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Open Access Articles

Title

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

PubMed ID

18593928

Authors

Connie Wing-Ching Lee, University of Massachusetts Medical School
Christopher M. Raskett, University of Massachusetts Medical School
Igor Prudovsky, Maine Medical Center Research Institute
Dario C. Altieri, University of Massachusetts Medical School

UMMS Affiliation

Department of Cancer Biology and the Cancer Center

Date

7-3-2008

Document Type

Article

Subjects

Adenocarcinoma; Amyloid Precursor Protein Secretases; Animals; Breast Neoplasms; Cell Proliferation; Cell Survival; Cells, Cultured; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Hela Cells; Humans; Mice; Mice, SCID; Microtubule-Associated Proteins; Neoplasm Proteins; Oligopeptides; Protease Inhibitors; Receptor, Notch1; Receptors, Notch; Signal Transduction; Xenograft Model Antitumor Assays

Disciplines

Life Sciences | Medicine and Health Sciences

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.