ErbB2 Induces Notch1 Activity and Function in Breast Cancer Cells

被引：36

作者：

Lindsay, Jaime ^{[1
]}

Jiao, Xuanmao ^{[1
]}

Sakamaki, Toshiyuki ^{[2
,3
]}

Casimiro, Mathew C. ^{[1
]}

Shirley, Lawrence A. ^{[4
]}

Tran, Thai H. ^{[1
]}

Ju, Xiaoming ^{[1
]}

Liu, Manran ^{[1
]}

Li, Zhiping ^{[1
]}

Wang, Chenguang ^{[1
]}

Katiyar, Sanjay ^{[1
]}

Rao, Mahadev ^{[2
,3
]}

Allen, Kathleen G. ^{[4
]}

Glazer, Robert I. ^{[2
,3
]}

Ge, Changhui ^{[5
]}

Stanley, Pamela ^{[5
]}

Lisanti, Michael P. ^{[1
]}

Rui, Hallgeir ^{[1
]}

Pestell, Richard G. ^{[1
]}

机构：

[1] Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA

[2] Georgetown Univ, Sch Med, Dept Oncol, Washington, DC USA

[3] Lombardi Comprehens Canc Ctr, Washington, DC USA

[4] Thomas Jefferson Univ, Dept Surg, Philadelphia, PA 19107 USA

[5] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10467 USA

来源：

CTS-CLINICAL AND TRANSLATIONAL SCIENCE | 2008年 / 1卷 / 02期

关键词：

cancer biology; oncogenes; signal transduction;

D O I：

10.1111/j.1752-8062.2008.00041.x

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The ErbB2 (Her2/neu epidermal growth receptor family) oncogene is overexpressed in 30% to 40% of human breast cancers. Cyclin D1 is the regulatory subunit of the holoenzyme that phosphorylates and inactivates the retinoblastoma (pRb) tumor suppressor and is an essential downstream target of ErbB2-induced tumor growth. Herein, we demonstrate that ErbB2 induces the activity of the Notch signaling pathway. ErbB2 induction of DNA synthesis, contact-independent growth, and mammosphere induction required Notch1. ErbB2-induced cyclin D1 and cyclin D1 expression was sufficient to induce Notch1 activity, and conversely, genetic deletion of Notch1 in mammary epithelial cells using floxed Notch (Notch(fl/fl)) mice demonstrated that cyclin D1 is induced by Notch1. Genetic deletion of cyclin D1 or small interfering RNA (siRNA) to cyclin D1-reduced Notch1 activity and reintroduction of cyclin D1 into cyclin D1-deficient cells restored Notch1 activity through the inhibition of Numb, an endogenous inhibitor of Notch1 activity. Thus, cyclin D1 functions downstream as a genetic target of Notch1, amplifies Notch1 activity by repressing Numb, and identifies a novel pathway by which ErbB2 induces Notch1 activity via the induction of cyclin D1.

引用

页码：107 / 115

页数：9