Abstract

The importance of the tumor–associated stroma in cancer progression is clear. However, it remains uncertain whether early events in the stroma are capable of initiating breast tumorigenesis. Here, we show that in the mammary glands of non-tumor bearing mice, stromal-specific phosphatase and tensin homolog (Pten) deletion invokes radiation-induced genomic instability in neighboring epithelium. In these animals, a single dose of whole-body radiation causes focal mammary lobuloalveolar hyperplasia through paracrine epidermal growth factor receptor (EGFR) activation, and EGFR inhibition abrogates these cellular changes. By analyzing human tissue, we discover that stromal PTEN is lost in a subset of normal breast samples obtained from reduction mammoplasty, and is predictive of recurrence in breast cancer patients. Combined, these data indicate that diagnostic or therapeutic chest radiation may predispose patients with decreased stromal PTEN expression to secondary breast cancer, and that prophylactic EGFR inhibition may reduce this risk.

Details

Title
Stromal PTEN determines mammary epithelial response to radiotherapy
Author
Sizemore, Gina M 1 ; Balakrishnan, Subhasree 2   VIAFID ORCID Logo  ; Thies, Katie A 3 ; Hammer, Anisha M 4 ; Sizemore, Steven T 1   VIAFID ORCID Logo  ; Trimboli, Anthony J 3 ; Cuitiño, Maria C 3 ; Steck, Sarah A 5 ; Tozbikian, Gary 6 ; Kladney, Raleigh D 5 ; Shinde, Neelam 5 ; Das, Manjusri 5 ; Park, Dongju 2 ; Majumder, Sarmila 5 ; Krishnan, Shiva 7 ; Yu, Lianbo 8 ; Fernandez, Soledad A 8 ; Chakravarti, Arnab 1 ; Shields, Peter G 7 ; White, Julia R 1 ; Yee, Lisa D 9 ; Rosol, Thomas J 10 ; Ludwig, Thomas 2 ; Park, Morag 11 ; Leone, Gustavo 3 ; Ostrowski, Michael C 3   VIAFID ORCID Logo 

1  The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Radiation Oncology, The Ohio State University, Columbus, OH, USA 
2  The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA 
3  Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA 
4  The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA 
5  The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA 
6  Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA 
7  The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA 
8  Department of Biomedical Informatics’ Center for Biostatistics, The Ohio State University, Columbus, OH, USA 
9  Division of Surgical Oncology, Department of Surgery, City of Hope, Duarte, CA, USA 
10  Department of Molecular and Cellular Biology, College of Arts and Sciences, Ohio University, Athens, OH, USA 
11  Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada 
Pages
1-14
Publication year
2018
Publication date
Jul 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-05266-6
ProQuest document ID
2071156767
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.