Molecular dependence of estrogen receptor-negative breast cancer on a notch-survivin signaling axis.
Molecular dependence of estrogen receptor-negative breast cancer on a notch-survivin signaling axis.
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DOI：
10.1158/0008-5472.can-07-6673
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发表时间：
2008-07-01
期刊：
影响因子：
11.2
通讯作者：
Altieri DC
中科院分区：
文献类型：
--
作者：
Lee CW;Raskett CM;Prudovsky I;Altieri DC
尽管在乳腺癌的管理方面取得了进展，但临床上侵袭性疾病亚型的分子基础尚未得到很好的理解。在这里，我们表明，在雌激素受体（ER）阴性的乳腺癌细胞中的Notch发育信号的激活导致凋亡抑制因子和细胞周期调节因子生存素的直接转录上调。这种反应与有丝分裂时生存素表达增加、细胞增殖增强和细胞分裂时活力增强有关。相反，用肽基γ-分泌酶抑制剂靶向Notch信号传导抑制存活素水平，诱导凋亡，消除软琼脂中的集落形成，并抑制小鼠中的局部和转移性肿瘤生长，而没有器官或全身毒性。相反，ER+乳腺癌细胞或各种正常细胞类型对Notch刺激不敏感。因此，ER-乳腺癌细胞变得依赖于Notch-存活蛋白信号传导以在体内维持它们。该途径的治疗靶点可用于临床侵袭性ER-xs乳腺癌患者的个体化治疗。
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-xs breast cancer.