Abstract 3866: Inactivation of p53/PTEN confers a specific epigenetic profile regulated by IL6-SOCS3 signaling
Authors: Ouzounova Maria , Kim Gwangil , Davis April , Quraishi Ahmed A. , Tawakkol Nader , Kota Shalini , Wicha Max S. , Korkaya Hasan 
Published: May 2015

Recent studies by us and others suggested that activation of inflammatory feedback loop play critical role in metastasis and therapeutic resistance by regulating EMT/CSC phenotype. Of these cytokines, IL6 is a key regulator of inflammatory responses and orchestrates these physiological functions by controlling the Stat3/NF-kB pathway which is negatively regulated by the suppressor of cytokine signaling 3 (SOCS3). Consistent with these reports, we demonstrated in our preliminary data that SOCS3 is abundantly expressed in non-malignant MCF10A cells as well as in luminal and HER2+ tumors where it negatively regulates the IL6/Stat3/NF-kB signaling. In contrast, SOCS3 protein was undetectable in basal cluadin-low breast cancer cell lines and primary tumors which express substantially higher levels of IL6. We developed transformed MCF10A model by simultaneous knockdown of p53 and PTEN. In this model single p53 and PTEN deletions result in hyperplasia or DCIS-like lesions. Interestingly, SOCS3 protein expression was undetectable in MCF10A-p53-PTEN- cells compared to parental MCF10A, single p53 (MCF10A-p53-) or PTEN (MCF10A-PTEN-) deleted cells. We demonstrated that IL6 mediated Stat3/NF-kB signaling is negatively regulated by SOCS3 that strongly inhibited the IL6/Stat3/NF-kB pathway when overexpressed in MCF10A-p53-PTEN- cells. Moreover, enforced SOCS3 expression in these cells reduced the tumor growth and inhibited metastasis. Furthermore, loss of SOCS3 expression is strongly associated with increased risk of recurrent disease in breast cancer patients. We hypothesized that loss of SOCS3 in TNBCs results in activation of IL6 feedback loop which drives aggressive metastatic phenotype. Interestingly Stat3/NF-kB signaling drives expression of SOCS3 in response to inflammation and serves as negative feedback loop, although molecular mechanism of SOCS3 expression in cancer has not been investigated. IL6 signaling has been previously reported to be involved in epigenetic regulation. We therefore correlated the gene expression and methylation profile after enforced SOCS3 expression. Our analysis revealed that expression levels of a significant number of genes involved in transcription, migration and metabolism were reverted to those of the parental non transformed cells and their transcription was regulated by methylation. These results suggest that interplay between genetic and epigenetic changes during malignant transformation of mammary epithelial cells may activate multiple signaling cascades and reconstitution of SOCS3 may have therapeutic utility in TNBC.

Citation Format: Maria Ouzounova, Gwangil Kim, April Davis, Ahmed A. Quraishi, Nader Tawakkol, Shalini Kota, Max S. Wicha, Hasan Korkaya. Inactivation of p53/PTEN confers a specific epigenetic profile regulated by IL6-SOCS3 signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3866. doi:10.1158/1538-7445.AM2014-3866