Although p53 mutations are found in ~50% of all human cancers, p53 mutations in some cancer types (such as breast cancer) constitute much lower percentage. The p53 functions among the cancers with wild type p53 can be circumvented by other mechanisms. The identification of these alternative mechanisms by which p53 tumor suppressing function is impaired can provide further insights into the molecular mechanisms of oncogenesis for the large portion of cancers harboring wild type p53. Recent studies suggested that the binding of the wild type p53 with its target promoter DNA sequences, and the trans-activation activity of wild type p53 are severely inhibited when the BCCIP gene is down-regulated. Furthermore, lack of BCCIP expression is associated with a poor clinical outcome in a set of cancer with wild type p53 but not among cancers with mutant p53. BCCIP expression is absent in 33% of breast cancer, and the BCCIP negativity is associated with wild type p53 in breast cancer. These clinical data are consistent with the finding that BCCIP defect may alleviate the function of wild type p53 function, and suggested that p53 and BCCIP are functionally in the same epistatic pathway to modulate the outcomes of cancer treatment and development of a subset of breast cancers. Based on these studies, we hypothesize that BCCIP defect represents a new mechanism to inactivate the p53 tumor suppressor activity, and plays a role in breast cancer development.
Aim 1 tests the working hypothesis that BCCIP is required for p53 binding to targeted promoters. When BCCIP is impaired, p53 is not able to form tetramer efficiently thus cannot function properly as a tumor suppressor.
Aim 2 will develop two mammary tumorigenesis models to address the role of BCCIP defect in breast cancer development, especially in triple negative breast cancer and the breast cancers that are p53 wild type. Because BCCIP down-regulation is found in a large fraction of breast cancers, and BCCIP defect may confer resistance to therapeutic DNA damage by abrogating the wild type p53 functions, we believe that this study has a great potential to further understand the molecular mechanism of oncogenesis, especially for these cancers with wild type p53, and thus would have significant impact on improving cancer intervention.

Public Health Relevance

It is well established that the status of tumor suppressor p53 in cancer is a major factor dictating the tumorigenesis and therapeutic outcomes. Our study will address the mechanisms and the consequences of BCCIP defect in alleviating wild type p53 tumor suppressor function. Because lack of BCCIP expression is found in a significant portion of human cancer (for example ~33% of breast cancer based on our preliminary studies) and ~50% of all human cancers do not have p53 mutation, our study will reveal a molecular oncogenesis mechanism relevant to a large portion of human cancers, and offer the scientific bases for further development of cancer intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA156706-02S1
Application #
8527931
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Ogunbiyi, Peter
Project Start
2011-03-14
Project End
2016-02-28
Budget Start
2012-08-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$45,527
Indirect Cost
$14,077
Name
University of Medicine & Dentistry of NJ
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Droz-Rosario, Roberto; Lu, Huimei; Liu, Jingmei et al. (2017) Roles of BCCIP deficiency in mammary tumorigenesis. Breast Cancer Res 19:115
Huhn, S C; Liu, J; Ye, C et al. (2017) Regulation of spindle integrity and mitotic fidelity by BCCIP. Oncogene 36:4750-4766
Ba, Qian; Li, Xiaoguang; Huang, Chao et al. (2017) BCCIP? modulates the ribosomal and extraribosomal function of S7 through a direct interaction. J Mol Cell Biol 9:209-219
Zhang, Cen; Liu, Juan; Huang, Grace et al. (2016) Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev 30:1956-70
Yu, Haiyang; Yue, Xuetian; Zhao, Yuhan et al. (2014) LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers. Nat Commun 5:5218
Yue, Jingyin; Huhn, Steven; Shen, Zhiyuan (2013) Complex roles of filamin-A mediated cytoskeleton network in cancer progression. Cell Biosci 3:7
Jiang, Xi; Yue, Jingyin; Lu, Huimei et al. (2013) Inhibition of filamin-A reduces cancer metastatic potential. Int J Biol Sci 9:67-77
Huang, Yi-Yuan; Dai, Li; Gaines, Dakim et al. (2013) BCCIP suppresses tumor initiation but is required for tumor progression. Cancer Res 73:7122-33
Shen, Zhiyuan; Huhn, Steven C; Haffty, Bruce G (2013) Escaping death to quiescence: avoiding mitotic catastrophe after DNA damage. Cell Cycle 12:1664
Yue, Jingyin; Lu, Huimei; Lan, Shijie et al. (2013) Identification of the DNA repair defects in a case of Dubowitz syndrome. PLoS One 8:e54389

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