Session: SAT 358-380-Steroid Hormone Biosynthesis & Metabolism
Poster Board SAT-367
Methods: Primary human ASCs, isolated from breast reduction surgery, were treated with PGE2 or PGE2 mimetic FSK/PMA and/or RITA (to stabilize p53). Aromatase, p53 and 18s or beta-actin (housekeeping gene) transcript expression was examined by real-time PCR. Reporter assays were performed to determine the effect of different treatments on PII and p53 activities in HEK293 cells and mammary preadipocytes (3T3L1 cells). Immunofluorescence was performed in ASCs to determine the effect of PGE2 on p53 subcellular localization and in clinical samples to compare the expression of p53 in tumor-free and tumor-bearing-breast tissue.
Results: RITA-stabilized p53 significantly reduced the PGE2 or FSK/PMA-induced aromatase expression and PII activity. FSK/PMA treatment significantly decreased p53 transcript and protein expression, as well as p53 transcriptional activity. ChIP demonstrated that p53 interacts with PII under basal conditions and that this interaction is decreased with FSK/PMA. Immunofluorescence showed that FSK/PMA and PGE2 treatment decreased p53 nuclear expression in hASC. In clinical samples, nuclear p53 expression was lower in tumor-bearing breast tissue compared to cancer free, and there was a positive correlation between perinuclear (inactive) p53 and aromatase fluorescence intensity.
Conclusion: Our findings describe the inhibition of p53 by tumor-derived factor PGE2 in the breast adipose stroma and provide a possible mechanism for the observation that p53 is decreased in tumor-associated stromal cells. Combined with results demonstrating that p53 is inhibitory of aromatase expression, our work provides a novel mechanism for the inflammatory-factor mediated production of estrogens in breast cancer.
Nothing to Disclose: LW, MD, SH, ERS, KAB
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