The goal of this project is to understand better the mechanisms of intrinsic tumor suppression that inhibit cells carrying oncogenic mutations from developing into clinically significant cancers. This suppression is of limited efficacy in preventing basal cell carcinogenesis, as it is by far the most common human cancer. Nonetheless mouse modeling indicates the presence of very strong p53-dependent anti-BCC effects, and human BCCs routinely carry p53 mutations. We (i) will investigate the connections by which mutation-driven activated hedgehog signaling, the pivotal abnormality in BCC carcinogenesis, activates p53's anti-cancer effects (ii) will elucidate the differences between the pro-carcinogenic effects of p53 loss of function mutations (as occur in human BCCs in PTCH1/basal cell nevus syndrome patients) and p53 gain of function mutations (as occur in human BCCs occurring sporadically) and (iii) will compare the effects of p53-dependent tumor suppression on the hair follicle tissue stem cells carrying mutations of hedgehog signaling vs. carrying mutant alleles activating oncogenic pathways that commonly underlie cancers of other tissues but not of skin. Successful prosecution of this Project will help elucidate why this "outlier" cancer is so common, why different genetic backgrounds can influence the type of p53 mutation found, and why specific tissues and cells are transformed by characteristic oncogenic pathways.

Public Health Relevance

Basal cell carcinomas in some populations are as common as all other cancers combined but the reasons for this high frequency remain cryptic, as does the relative lack of other types of cancers arising from the same tissue cell of origin. Our project will address these clinical characteristics using newer understandings of mechanisms of intrinsic tumor suppression that prevent cells carrying oncogenic mutations from developing into clinically significant cancers. Hence study of resistance to this common cancer can point to new ways for prevention not only these skin cancers but potentially of visceral cancers as well.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163611-02
Application #
8450702
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Okano, Paul
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$315,981
Indirect Cost
$120,931
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609