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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 | Michael C Ostrowski
Nature communications | 2018

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.

Pubmed ID: 30018330

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: K22 CA218472
  • Agency: U.S. Department of Defense (DOD), International
    Id: W81XWH-14-1-0040
  • Agency: U.S. Department of Health & Human Services | National Institutes of Health (NIH), International
    Id: P01CA097189
  • Agency: NCI NIH HHS, United States
    Id: P30 CA138313
  • Agency: NCI NIH HHS, United States
    Id: K22 CA218459
  • Agency: NCI NIH HHS, United States
    Id: P01 CA097189
  • Agency: NCI NIH HHS, United States
    Id: R01 CA121275
  • Agency: NCI NIH HHS, United States
    Id: P30 CA016058

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