Esophageal squamous cell carcinoma (ESCC) predominantly affects African Americans rather than Caucasian Americans at a ratio of about 4:1. African American patients with ESCC have much worse prognosis than their Caucasian counterparts. Therefore it is important to better understand molecular mechanisms of ESCC and develop targeted therapy for this deadly disease in order to reduce racial disparity. Recent NextGen sequencing studies have identified multiple driver mutations in human ESCC among which Nrf2 and Keap1 mutations are known to activate Nrf2 signaling. However, the molecular mechanisms of Nrf2-associated carcinogenesis have not been clearly understood particularly in vivo. Based on our preliminary data, we hypothesize that Nrf2 activation induces esophageal hyperproliferation and hyperkeratosis through the EGFR/PI3K/Akt pathway and metabolic reprogramming. Using the Keap1-/- mouse model of esophageal hyperproliferation and hyperkeratosis, we plan to test our hypothesis with two specific aims: (1) To examine whether Nrf2 activation in Keap1-/- esophagus activates the EGFR/PI3K/Akt pathway and metabolic reprogramming through transcriptional regulation of genes of the EGFR/PI3K/Akt pathway and energy metabolism. (2)To test whether genetic or chemical inhibition of the EGFR/PI3K/Akt pathway or metabolic reprogramming may suppress esophageal phenotype in Keap1-/- mice, and whether inhibition of both events may have synergistic effect. This Pilot Project is aimed to understand the carcinogenic mechanisms of Nrf2 activation in esophageal squamous cell carcinogenesis in vivo. If successful, it will lay down a solid foundation for translational studies on Nrf2-high ESCC and contribute to reduction of cancer health disparity in the African American population.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-PCRB-C (O1))
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University of North Carolina Chapel Hill
Chapel Hill
United States
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Puvanesarajah, Samantha; Nyante, Sarah J; Kuzmiak, Cherie M et al. (2018) PAM50 and Risk of Recurrence Scores for Interval Breast Cancers. Cancer Prev Res (Phila) 11:327-336
DeBono, Nathan L; Robinson, Whitney R; Lund, Jennifer L et al. (2018) Race, Menopausal Hormone Therapy, and Invasive Breast Cancer in the Carolina Breast Cancer Study. J Womens Health (Larchmt) 27:377-386
Smith, Jennifer S; Des Marais, Andrea C; Deal, Allison M et al. (2018) Mailed Human Papillomavirus Self-Collection With Papanicolaou Test Referral for Infrequently Screened Women in the United States. Sex Transm Dis 45:42-48
Williams, Lindsay A; Nichols, Hazel B; Hoadley, Katherine A et al. (2018) Reproductive risk factor associations with lobular and ductal carcinoma in the Carolina Breast Cancer Study. Cancer Causes Control 29:25-32
Troester, Melissa A; Sun, Xuezheng; Allott, Emma H et al. (2018) Racial Differences in PAM50 Subtypes in the Carolina Breast Cancer Study. J Natl Cancer Inst 110:
Anderson, Chelsea; Breithaupt, Lindsay; Des Marais, Andrea et al. (2018) Acceptability and ease of use of mailed HPV self-collection among infrequently screened women in North Carolina. Sex Transm Infect 94:131-137
Kilfoyle, Kimberly A; Des Marais, Andrea C; Ngo, Mai Anh et al. (2018) Preference for Human Papillomavirus Self-Collection and Papanicolaou: Survey of Underscreened Women in North Carolina. J Low Genit Tract Dis 22:302-310
Xiong, Zhaohui; Ren, Shuang; Chen, Hao et al. (2018) PAX9 regulates squamous cell differentiation and carcinogenesis in the oro-oesophageal epithelium. J Pathol 244:164-175
Butler, EboneƩ N; Bensen, Jeannette T; Chen, Mengjie et al. (2018) Prediagnostic Smoking Is Associated with Binary and Quantitative Measures of ER Protein and ESR1 mRNA Expression in Breast Tumors. Cancer Epidemiol Biomarkers Prev 27:67-74
Jiang, Ming; Li, Haiyan; Zhang, Yongchun et al. (2017) Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus. Nature 550:529-533

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