title: ErbB2 induces Notch1 activity and function in breast cancer cells.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Lindsay
authors.forename: Xuanmao
authors.initials: X
authors.lastname: Jiao
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakamaki
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Shirley
authors.forename: Thai H
authors.initials: TH
authors.lastname: Tran
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ju
authors.forename: Manran
authors.initials: M
authors.lastname: Liu
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Sanjay
authors.initials: S
authors.lastname: Katiyar
authors.forename: Mahadev
authors.initials: M
authors.lastname: Rao
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Allen
authors.forename: Robert I
authors.initials: RI
authors.lastname: Glazer
authors.forename: Changhui
authors.initials: C
authors.lastname: Ge
authors.forename: Pamela
authors.initials: P
authors.lastname: Stanley
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: 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
chemical_list: 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