TY - JOUR
T1 - ErbB2 induces Notch1 activity and function in breast cancer cells
AU - Lindsay, Jaime
AU - Jiao, Xuanmao
AU - Sakamaki, Toshiyuki
AU - Casimiro, Mathew C.
AU - Shirley, Lawrence A.
AU - Tran, Thai H.
AU - Ju, Xiaoming
AU - Liu, Manran
AU - Li, Zhiping
AU - Wang, Chenguang
AU - Katiyar, Sanjay
AU - Rao, Mahadev
AU - Allen, Kathleen G.
AU - Glazer, Robert I.
AU - Ge, Changhui
AU - Stanley, Pamela
AU - Lisanti, Michael P.
AU - Rui, Hallgeir
AU - Pestell, Richard G.
PY - 2008
Y1 - 2008
N2 - 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 (Notchfl/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.
AB - 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 (Notchfl/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.
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U2 - 10.1111/j.1752-8062.2008.00041.x
DO - 10.1111/j.1752-8062.2008.00041.x
M3 - Article
C2 - 20443831
AN - SCOPUS:75149125614
SN - 1752-8054
VL - 1
SP - 107
EP - 115
JO - Clinical and Translational Science
JF - Clinical and Translational Science
IS - 2
ER -
