The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer.

Authors

A K Witkiewicz, Department of Pathology, UT Southwestern Medical Center, Simmons Cancer Center, UT Southwestern Medical CenterFollow
D W Cox, Department of Pathology, UT Southwestern Medical Center
D Rivadeneira, Department of Cancer Biology, Thomas Jefferson UniversityFollow
Adam Ertel, Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PAFollow
Paolo Fortina, Department of Cancer Biology, Thomas Jefferson UniversityFollow
Gordon Schwartz, MD, MBA, FACS, Department of Surgery, Thomas Jefferson UniversityFollow
E S Knudsen, Department of Pathology, UT Southwestern Medical Center, Simmons Cancer Center, UT Southwestern Medical CenterFollow

Document Type

Article

Publication Date

7-24-2014

Comments

This article has been peer reviewed. It was published in: Oncogene.

Volume 33, Issue 30, 24 July 2014, Pages 3980-3991.

The published version is available at DOI: 10.1038/onc.2013.367

Copyright © 2014 Macmillan Publishers Limited.

Abstract

The processes that control the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer remain poorly understood. Epidermal growth factor receptor 2 (ErbB2) overexpression is common in DCIS, as is disruption of the retinoblastoma tumor suppressor (RB) pathway. Here, we examined the cooperative impact of ErbB2 and RB deregulation on facets of disease progression. Our studies demonstrate that RB deficiency altered the expression of key molecules needed for proper cellular organization and epithelial cell-cell adhesion as part of a program related to the epithelial-to-mesenchymal transition (EMT). An increase in the invasive potential of ErbB2-overexpressing cells was observed upon RB depletion. Further, stable knockdown of RB resulted in invasive lesions in orthotopic xenograft assays, compared with DCIS-like lesions developing from RB-proficient cells. Conversely, the invasive phenotype observed in ErbB2-positive cancer models was inhibited through CDK4/6 inhibition in an RB-dependent manner. Finally, in a cohort of DCIS cases, we show that, although elevated levels of ErbB2 are associated with increased risk of a subsequent DCIS recurrence, it is not associated with progression to invasive disease. In contrast, RB loss in ErbB2-positive DCIS cases was associated with increased risk for invasive breast cancer. Taken together, these data demonstrate a key role for the RB pathway in invasion associated with breast tumor progression, and shed light on the key molecular events that promote the progression of DCIS to invasive disease.

Recommended Citation

Witkiewicz, A K; Cox, D W; Rivadeneira, D; Ertel, Adam; Fortina, Paolo; Schwartz, MD, MBA, FACS, Gordon; and Knudsen, E S, "The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer." (2014). Department of Cancer Biology Faculty Papers. Paper 73.
https://jdc.jefferson.edu/cbfp/73

PubMed ID

24121271