Stromal PTEN determines mammary epithelial response to radiotherapy.
Gina M SizemoreSubhasree BalakrishnanKatie A ThiesAnisha M HammerSteven T SizemoreAnthony J TrimboliMaria C CuitiñoSarah A SteckGary TozbikianRaleigh D KladneyNeelam ShindeManjusri DasDongju ParkSarmila MajumderShiva KrishnanLianbo YuSoledad A FernandezArnab ChakravartiPeter G ShieldsJulia R WhiteLisa D YeeThomas J RosolThomas LudwigMorag ParkGustavo LeoneMichael C OstrowskiPublished in: 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.
Keyphrases
- epidermal growth factor receptor
- radiation induced
- tyrosine kinase
- bone marrow
- pi k akt
- cell proliferation
- advanced non small cell lung cancer
- small cell lung cancer
- radiation therapy
- endothelial cells
- signaling pathway
- poor prognosis
- papillary thyroid
- early stage
- squamous cell carcinoma
- type diabetes
- long non coding rna
- electronic health record
- metabolic syndrome
- squamous cell
- protein kinase
- skeletal muscle
- insulin resistance
- high fat diet induced
- locally advanced
- breast cancer risk