ErbB2 induces Notch1 activity and function in breast cancer cells.
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 suficient to induce Notch1 activity, and conversely, genetic deletion of Notch1 in mammary epithelial cells using foxed 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.
Lindsay
Jaime
J
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Jiao
Xuanmao
X
Sakamaki
Toshiyuki
T
Casimiro
Mathew C
MC
Shirley
Lawrence A
LA
Tran
Thai H
TH
Ju
Xiaoming
X
Liu
Manran
M
Li
Zhiping
Z
Wang
Chenguang
C
Katiyar
Sanjay
S
Rao
Mahadev
M
Allen
Kathleen G
KG
Glazer
Robert I
RI
Ge
Changhui
C
Stanley
Pamela
P
Lisanti
Michael P
MP
Rui
Hallgeir
H
Pestell
Richard G
RG
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005260:Female; D006801:Humans; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D014410:Tumor Stem Cell Assay
D053829:Amyloid Precursor Protein Secretases; D019938:Cyclin D1; D004273:DNA, Neoplasm; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D051881:Receptor, Notch1; C508053:ERBB2 protein, human