Indiana University-Purdue University Indianapolis (IUPUI) / Chronic inflammation is a major driver of tumor progression in over fifty
percent of breast cancers. Tumors activate inflammatory processes by secreting
factors that recruit and trigger inflammatory cells to release cytokines such as
Interleukin 6 (IL-6). IL-6 stimulates the activity of signal transducers and
activators of transcription 3 (STAT3), a transcription factor that has been
extensively studied for its role in promoting breast cancer. Recently,
downregulated HIPPO signaling was shown to drive the pro-growth effects of IL
6. Reduced HIPPO signaling allows for the nuclear translocation of
transcriptional co-activator yes associated protein (YAP), implicating IL-6 in the
co-activation of several transcription factors such as the TEADs that trigger pro
growth programs. While IL-6/STAT3 stimulation has been shown to increase
YAP activity, the mechanism driving this remains undocumented. The
Angiomotins (Amots) are adapters of the HIPPO pathway that directly bind and
regulate YAP activity. Molecular characterization of Amot transcriptional
regulation unexpectedly revealed a single promoter controlling the expression of
its two major isoforms: Amot 130 and Amot 80. Through immunofluorescent
analysis, this study found that total Amot levels were elevated across multiple
breast tumor subtypes and highest in samples with increased presence of
stromal inflammatory cells. Further, the induction of total Amot expression by IL
6 was found to be essential for YAP dependent growth of breast cancer cells. The activation of Amot transcription by IL-6 was found to be through Specificity
Protein 1 (Sp1), a transcription factor that is activated by STAT3. This work
connects the activation of YAP1 by IL-6/STAT3 through the elevation of Amot
expression by Sp1. Taken together, this explains a new avenue whereby breast
cancer cells acquire enhanced oncogenic properties in response to inflammatory signaling.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/12088 |
| Date | 16 June 2016 |
| Creators | Bringman, Lauren R. |
| Contributors | Wells, Clark |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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