No abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor constitutively activated in many cancer types, and has been identified as a major mediator of cancer stemness (Li et.al., PNAS 2015). The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) is the reactive oxygen species (ROS) sensor and a master regulator of antioxidant gene expression. NRF2 has recently been implicated in contributing to cancer stem cell phenotypes, chemoresistance, and is associated with poor clinical prognosis. Hypoxia is considered a major feature of the tumor microenvironment as it can promote tumor progression, increased stemness characteristic, and resistance to conventional therapeutic intervention. Hypoxia can regulate a series of stress-sensor transcription factors, notably, the reactive oxygen species (ROS) sensor and response modulator NRF2. We studied NRF2 transcript and protein levels in breast cancer cell lines MCF7 and AU565 cells under both hypoxic and normoxic conditions. Our data shows that in response to STAT3 pathway activators, NRF2 is upregulated at both mRNA and protein levels under hypoxia and this upregulation is STAT3 dependent. NRF2 ChIP-Seq experiments demonstrate that both hypoxia and STAT3 stimulation can modulate NRF2 binding in MCF-7 breast cancer cells. Surprisingly, under hypoxic conditions, STAT3 activation dramatically enhances (10 fold) NRF2 binding sites across the genome. Downstream analysis of NRF2 target genes revealed a significant change from stress response to activation of gene signaling pathways involved in stemness-high cancer cells and metastatic cells under both hypoxic and STAT3 stimulation. Finally, we investigated whether the stemness inhibitor BBI-608 (Napabucasin) could reduce chemotherapy-induced NRF2 upregulation. Our results indicate that STAT3 modulates NRF2 levels and transcriptional activity, and that stemness inhibitor BBI-608 can prevent this upregulation. Our data revealed STAT3-NRF2-Hypoxia as a novel reinforcing regulatory mechanism for promoting cancer stemness and chemoresistance. Citation Format: Luz Elisa Tavera, Karen Simon, Juying Li, Katherine Geromini, Zhuo Zhang, Sarah Keates, Harry A. Rogoff, Chiang J. Li. Identification of STAT3-NRF2-hypoxia as a novel reinforcing mechanism for promoting cancer stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-143. doi:10.1158/1538-7445.AM2017-LB-143

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3), regulates gene expression through the vitamin D receptor (VDR). Even though 1,25D3 is still best known as a regulator of bodily calcium homeostasis, 1,25D3 has a plethora of physiological actions which include immune and nervous system modulation, cellular proliferation and differentiation. Epidemiological and model studies have revealed the cancer-protective properties of 1,25D3 in colon, prostate and notably in breast. We are actively investigating the anti-proliferative properties of 1,25D3 in a panel of human breast cancer cell lines. We found that 1,25D3 induces autophagy in several luminal-like breast cancer cell models, but not in basal-like or mesenchymal-like models. We performed VDR and signaling partner RXR whole-genome ChIP-seq analysis to uncover all of the direct 1,25D3 target genes involved in regulation of metabolism and autophagy. Our studies suggest that energy regulation as an important aspect of 1,25D3 anti-proliferative properties in luminal-like breast cancer cells. Citation Format: Luz E. Tavera, Thomas Westerling, Myles Brown. Genome-wide analysis of the vitamin D receptor (VDR) binding sites reveals vitamin D role modulating autophagy and metabolism in luminal-like breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3562. doi:10.1158/1538-7445.AM2013-3562

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3), regulates gene expression through the vitamin D receptor (VDR). Even though 1,25D3 is still best known as a regulator of bodily calcium homeostasis, 1,25D3 has a plethora of physiological actions which include immune and nervous system modulation, cellular proliferation and differentiation. Epidemiological and model studies have revealed the cancer-protective properties of 1,25D3 in colon, prostate and notably in breast. We are actively investigating the anti-proliferative properties of 1,25D3 in a panel of human breast cancer cell lines. We found that 1,25D3 induces autophagy in several luminal-like breast cancer cell models, but not in basal-like or mesenchymal-like models. We performed VDR and signaling partner RXR whole-genome ChIP-seq analysis to uncover all of the direct 1,25D3 target genes involved in regulation of metabolism and autophagy. Our preliminary studies suggest that energy regulation as an important aspect of 1,25D3 anti-proliferative properties in luminal-like breast cancer cells Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-275. doi:1538-7445.AM2012-LB-275