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

doi:10.1111/j.1752-8062.2008.00041.x

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

Cell Biology

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

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 (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.

Original language	English (US)
Pages (from-to)	107-115
Number of pages	9
Journal	Clinical and Translational Science
Volume	1
Issue number	2
DOIs	https://doi.org/10.1111/j.1752-8062.2008.00041.x
State	Published - 2008

Keywords

Cancer biology
Oncogenes
Signal transduction

ASJC Scopus subject areas

General Pharmacology, Toxicology and Pharmaceutics
General Biochemistry, Genetics and Molecular Biology
General Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/j.1752-8062.2008.00041.x

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Lindsay, J., Jiao, X., Sakamaki, T., Casimiro, M. C., Shirley, L. A., Tran, T. H., Ju, X., Liu, M., Li, Z., Wang, C., Katiyar, S., Rao, M., Allen, K. G., Glazer, R. I., Ge, C., Stanley, P., Lisanti, M. P., Rui, 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

Lindsay, J, Jiao, X, Sakamaki, T, Casimiro, MC, Shirley, LA, Tran, TH, Ju, X, Liu, M, Li, Z, Wang, C, Katiyar, S, Rao, M, Allen, KG, Glazer, RI, Ge, C, Stanley, P, Lisanti, MP, Rui, H & Pestell, RG 2008, 'ErbB2 induces Notch1 activity and function in breast cancer cells', Clinical and Translational Science, vol. 1, no. 2, pp. 107-115. https://doi.org/10.1111/j.1752-8062.2008.00041.x

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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 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.",

keywords = "Cancer biology, Oncogenes, Signal transduction",

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

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doi = "10.1111/j.1752-8062.2008.00041.x",

language = "English (US)",

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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.

KW - Cancer biology

KW - Oncogenes

KW - Signal transduction

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SN - 1752-8054

VL - 1

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EP - 115

JO - Clinical and Translational Science

JF - Clinical and Translational Science

IS - 2

ER -

ErbB2 induces Notch1 activity and function in breast cancer cells

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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