Aromatase expression is inhibited by tumour suppressor p53 and PGE2 down regulates p53 in breast tumour associated adipose stromal cells — ASN Events
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  3. Aromatase expression is inhibited by tumour suppressor p53 and PGE2 down regulates p53 in breast tumour associated adipose stromal cells

Aromatase expression is inhibited by tumour suppressor p53 and PGE2 down regulates p53 in breast tumour associated adipose stromal cells (#310)

Xuyi Wang 1 2 , Maria Docanto 1 , Seungmin Ham 1 , Evan R. Simpson 1 3 , Kristy Brown 1 2
  1. Prince Henry's Institute, Clayton, VIC, Australia
  2. Physiology Department, Monash University, Melbourne, Australia
  3. Biochemistry & Molecular Biology Department, Monash University, Melbourne, Australia

Background: Locally produced oestrogens are required for the proliferation of postmenopausal breast cancers. Aromatase converts androgens into oestrogens and its expression in breast adipose stromal cells (ASCs) is increased in response to tumour-derived factors such as prostaglandin E2 (PGE2) via the activation of aromatase promoter II (PII). Women with breast cancer often carry sporadic mutations in tumour suppressor p53. However, mutations in p53 in ASCs are infrequent. This study aimed to determine the effect of p53 on aromatase expression and how PGE2 regulates p53 in human ASCs in the context of postmenopausal breast cancer.

Methods: Primary human ASCs were treated with PGE2 or the PGE2 mimetic FSK/PMA and/or RITA (to stabilise p53). Aromatase and p53 transcript expression was examined by real-time PCR, p53 protein expression and posttranslational modifications were examined by Western blotting and ChIP was used to demonstrate p53 binding to aromatase PII in ASCs. Reporter assays were performed to determine the effect of p53 on PII activity in 3T3-L1 preadipocytes. Immunofluorescence was performed to determine the effect of PGE2 on p53 subcellular localisation in ASCs and in clinical samples to compare the expression of p53 in tumour-free and tumour-bearing-breast tissue.

Results: PGE2 significantly decreased p53 transcript and protein expression, as well as p53 posttranslational modifications, nuclear localisation, and transcriptional activity. RITA-stabilised p53 significantly reduced the PGE2 or FSK/PMA-induced aromatase expression and PII activity. ChIP demonstrated that p53 interacts with PII under basal conditions and that this interaction is decreased with PGE2. In clinical samples, nuclear p53 expression was lower in tumour-bearing breast tissue compared to cancer free, and there was a positive correlation between perinuclear (inactive) p53 and aromatase fluorescence intensity.

Conclusion: Our findings demonstrate that p53 is inhibitory of aromatase expression and we provide a novel mechanism for the inflammatory-factor mediated production of estrogens in breast cancer.

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