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

CW Lee, CM Raskett, I Prudovsky, DC Altieri - Cancer research, 2008 - AACR
CW Lee, CM Raskett, I Prudovsky, DC Altieri
Cancer research, 2008AACR
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 …
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]
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