Stromal PTEN determines mammary epithelial response to radiotherapy

Gina M. Sizemore, Subhasree Balakrishnan, Katie A. Thies, Anisha M. Hammer, Steven T. Sizemore, Anthony J. Trimboli, Maria C. Cuitiño, Sarah A. Steck, Gary Tozbikian, Raleigh D. Kladney, Neelam Shinde, Manjusri Das, Dongju Park, Sarmila Majumder, Shiva Krishnan, Lianbo Yu, Soledad A. Fernandez, Arnab Chakravarti, Peter G. Shields, Julia R. White, Lisa D. Yee, Thomas J. Rosol, Thomas Ludwig, Morag Park, Gustavo Leone () and Michael C. Ostrowski ()
Additional contact information
Gina M. Sizemore: The Ohio State University
Subhasree Balakrishnan: The Ohio State University
Katie A. Thies: Medical University of South Carolina
Anisha M. Hammer: The Ohio State University
Steven T. Sizemore: The Ohio State University
Anthony J. Trimboli: Medical University of South Carolina
Maria C. Cuitiño: Medical University of South Carolina
Sarah A. Steck: The Ohio State University
Gary Tozbikian: The Ohio State University Wexner Medical Center
Raleigh D. Kladney: The Ohio State University
Neelam Shinde: The Ohio State University
Manjusri Das: The Ohio State University
Dongju Park: The Ohio State University
Sarmila Majumder: The Ohio State University
Shiva Krishnan: The Ohio State University
Lianbo Yu: The Ohio State University
Soledad A. Fernandez: The Ohio State University
Arnab Chakravarti: The Ohio State University
Peter G. Shields: The Ohio State University
Julia R. White: The Ohio State University
Lisa D. Yee: City of Hope
Thomas J. Rosol: Ohio University
Thomas Ludwig: The Ohio State University
Morag Park: McGill University
Gustavo Leone: Medical University of South Carolina
Michael C. Ostrowski: Medical University of South Carolina

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05266-6

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