Stromal PTEN determines mammary epithelial response to radiotherapy
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 17, 2018
- Source ID
- 10.1038/s41467-018-05266-6
Entities
People
- Anisha M. Hammer
- Anthony J. Trimboli
- Arnab Chakravarti
- Dongju Park
- Gary Tozbikian
- Gina M. Sizemore
- Gustavo Leone
- Julia R. White
- Katie A. Thies
- Lianbo Yu
- Lisa D Yee
- Manjusri Das
- Maria C. Cuitiño
- Michael C. Ostrowski
- Morag Park
- Neelam Shinde
- Peter G. Shields
- Raleigh D. Kladney
- Sarah A. Steck
- Sarmila Majumder
- Shiva Krishnan
- Soledad A. Fernandez
- Steven T Sizemore
- Subhasree Balakrishnan
- Thomas J. Rosol
- Thomas Ludwig
Organizations
- National Institutes of Health
- United States Department of Defense