Faculty Collaboration Database

Selective roles of E2Fs for ErbB2- and Myc-mediated mammary tumorigenesis. Oncogene 2015 Jan 02;34(1):119-28

Date

11/28/2013

Pubmed ID

24276244

Pubmed Central ID

PMC4032808

DOI

10.1038/onc.2013.511

Scopus ID

2-s2.0-84964314758 (requires institutional sign-in at Scopus site)   27 Citations

Abstract

Previous studies have demonstrated that cyclin D1, an upstream regulator of the Rb/E2F pathway, is an essential component of the ErbB2/Ras (but not the Wnt/Myc) oncogenic pathway in the mammary epithelium. However, the role of specific E2fs for ErbB2/Ras-mediated mammary tumorigenesis remains unknown. Here, we show that in the majority of mouse and human primary mammary carcinomas with ErbB2/HER2 overexpression, E2f3a is up-regulated, raising the possibility that E2F3a is a critical effector of the ErbB2 oncogenic signaling pathway in the mammary gland. We examined the consequence of ablating individual E2fs in mice on ErbB2-triggered mammary tumorigenesis in comparison to a comparable Myc-driven mammary tumor model. We found that loss of E2f1 or E2f3 led to a significant delay in tumor onset in both oncogenic models, whereas loss of E2f2 accelerated mammary tumorigenesis driven by Myc-overexpression. Furthermore, southern blot analysis of final tumors derived from conditionally deleted E2f3(-/loxP) mammary glands revealed that there is a selection against E2f3(-/-) cells from developing mammary carcinomas, and that such selection pressure is higher in the presence of ErbB2 activation than in the presence of Myc activation. Taken together, our data suggest oncogenic activities of E2F1 and E2F3 in ErbB2- or Myc-triggered mammary tumorigenesis, and a tumor suppressor role of E2F2 in Myc-mediated mammary tumorigenesis.

Author List

Wu L, de Bruin A, Wang H, Simmons T, Cleghorn W, Goldenberg LE, Sites E, Sandy A, Trimboli A, Fernandez SA, Eng C, Shapiro C, Leone G

Authors

Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin
Anthony J. Trimboli PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
Breast Neoplasms
Carcinogenesis
Cell Proliferation
E2F1 Transcription Factor
E2F2 Transcription Factor
E2F3 Transcription Factor
Female
Gene Deletion
Humans
Mammary Neoplasms, Animal
Mammary Neoplasms, Experimental
Mice
Phosphorylation
Proto-Oncogene Proteins c-myc
Receptor, ErbB-2
Signal Transduction