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Stromal PTEN determines mammary epithelial response to radio-therapy

ABSTRACT: It is well-described that the tumor stroma participates in cancer progression, but whether stromal factors can initiate breast tumorigenesis remains unclear. Using our previously described stromal-specific phosphatase and tensin homolog (PTEN) deletion mouse model, we investigated transformative events in young, non-tumor bearing animals. Here, we show stromal PTEN deletion initiates radiation-induced genomic instability on neighboring mammary epithelium through paracrine epidermal growth factor receptor (EGFR) activation. In these mice, a single low dose of whole-body radiation induces mammary hyperplasia, a result that is prevented by pre-treatment with an EGFR inhibitor. We reveal that stromal PTEN is lost in a subset of normal breast samples and is predictive of recurrence in breast cancer patients. Combined, these data suggest both diagnostic and therapeutic chest wall radiotherapy may inadvertently predispose patients with focal stromal PTEN loss to secondary breast cancer, and that this predisposition may be treated prophylactically through EGFR inhibition.

ORGANISM(S): Mus musculus

PROVIDER: GSE93784 | GEO | 2018/06/13

REPOSITORIES: GEO

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Project description:Abstract BACKGROUND: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. METHODS: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. RESULTS: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. CONCLUSIONS: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC. Gene expression profiles were generated for 95 breast tumors using Agilent Human 44K v5 microarrays following the manufacturer protocol. Stratagene Universal Human Reference RNA was used as the common control sample.

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Stromal PTEN determines mammary epithelial response to radio-therapy

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