ErbB2 induces Notch1 activity and function in breast cancer cells

Jaime Lindsay, Xuanmao Jiao, Toshiyuki Sakamaki, Mathew C. Casimiro, Lawrence A. Shirley, Thai H. Tran, Xiaoming Ju, Manran Liu, Zhiping Li, Chenguang Wang, Sanjay Katiyar, Mahadev Rao, Kathleen G. Allen, Robert I. Glazer, Changhui Ge, Pamela Stanley, Michael P. Lisanti, Hallgeir Rui, Richard G. Pestell

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)107-115
Number of pages9
JournalClinical and Translational Science
Volume1
Issue number2
DOIs
Publication statusPublished - 2008

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Lindsay, J., Jiao, X., Sakamaki, T., Casimiro, M. C., Shirley, L. A., Tran, T. H., ... Pestell, R. G. (2008). ErbB2 induces Notch1 activity and function in breast cancer cells. Clinical and Translational Science, 1(2), 107-115. https://doi.org/10.1111/j.1752-8062.2008.00041.x