SIM2s Regulation of the DNA Damage Response and Metabolic Adaptation in DCIS Progression

SIM2s Regulation of the DNA Damage Response and Metabolic Adaptation in DCIS Progression

Weston Porter, Ph.D
Texas A & M
Wed, 2/17/2016 - 4:00pm

221 Integrated Sciences Building

The incidence of breast ductal carcinoma in situ (DCIS) has increased dramatically as a result of screening mammography; however, there are gaps in our understanding of which lesions will become invasive and the mechanisms regulating recurrence and progression. Senescence and metabolism play key roles in breast cancer progression. Though bypass of senescence and metabolic adaptation are hallmarks of cancer progression, there is little if any evidence that these two critical pathways are mechanistically linked in DCIS progression. We have shown that Singleminded-2s (SIM2s; expressed from SIM2), a member of the bHLH/PAS family of transcription factors, is a tumor suppressor down-regulated in Transition from DCIS to IDC. Our recent results indicate that SIM2s is a potent inducer of senescence and the DNA damage response pathway and oxidative phosphorylation in breast cancer, and does so by directly regulating p21WAF1 independent of p53. Thus,suggesting that SIM2s is a tumor suppressor that blocks DCIS progression by regulating senescence-metabolic equilibrium.
Regulation of DCIS to invasive breast cancer progression by Singleminded-2s (SIM2s).
Scribner KC, Behbod F, Porter WW. Oncogene. 2013 May 23;32(21):2631-9. doi: 10.1038/onc.2012.286. Epub 2012 Jul 9.PMID: 22777354
Singleminded-2s (Sim2s) promotes delayed involution of the mouse mammary gland through suppression of Stat3 and NFκB.
Scribner KC, Wellberg EA, Metz RP, Porter WW.Mol Endocrinol. 2011 Apr;25(4):635-44. doi: 10.1210/me.2010-0423. Epub 2011 Feb 3. PMID: 21292822
The bHLH/PAS transcription factor singleminded 2s promotes mammary gland lactogenic differentiation. Wellberg E, Metz RP, Parker C, Porter WW. Development. 2010 Mar;137(6):945-52. doi: 10.1242/dev.041657. Epub 2010 Feb 11. PMID: 20150276

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