The CUL4A ubiquitin ligase gene is frequently amplified and/or overexpressed in breast cancer, hepatocellular carcinoma, mesothelioma and many other tumor types. CUL4A is also a direct transcriptional target of Wnt signaling, which is aberrantly activated in up to 63% of all breast cancers. Recent studies identified multiple substrates and cellular pathways that are subjected to ubiquitin-proteolytic control by CUL4A and are implicated in oncogenic transformation. However, the role of CUL4A in tumorigenesis remains unclear, and this knowledge gap is largely due to the lack of in vivo tumor models in which CUL4A expression can be manipulated in a temporal and tissue-specific manner during the course of tumor development. This proposal seeks to definitively determine the pathophysiological role of CUL4A in mammary tumorigenesis, and begins to dissect the specific ubiquitin-proteolytic events that underlie tumor initiation, maintenance, and resistance to camptothecin-type chemotherapy drugs. We are uniquely positioned to perform the proposed studies, as (1) we recently generated conditional CUL4A knockout mice that will overcome the limitations of unavailable experimental models, (2) we have at our disposal a well-established breast tumor bank with over 3,000 specimens, including over 250 triple negative breast cancer (TNBC) cases (CUL4A amplification was detected in ~20% TNBCs.), and patient clinico-pathological information, and (3) we discovered a novel function of the Cockayne syndrome A (CSA) DNA repair protein in CUL4 (CUL4A and its family member CUL4B)- dependent degradation of topoisomerase 1 (TOP1), implicating CUL4 dysregulation as a mechanism for resistance of tumor patients to TOP1-directed chemotherapy (e.g. camptothecin). We plan to test the hypothesis that CUL4A dysregulation promotes tumorigenesis and confers resistance to chemotherapy by pursuing two specific aims: (1) Determine the role and mechanistic basis of CUL4A in mammary tumor development and maintenance;(2) Delineate the mechanistic role of CUL4 dysregulation in tumor resistance to topoisomerase I inhibitor chemotherapy drugs. Successful completion of the proposed studies is anticipated to definitively establish the role of CUL4A- mediated ubiquitination in the pathogenesis of breast cancer, and shed light on the resistance of certain tumors to chemotherapy by camptothecin-type drugs. The evaluation of the efficacy of CUL4 inhibition using a combination of cell culture, mouse models and human breast cancer specimens is expected to facilitate the development of new and effective therapeutic strategies against breast cancer and other tumor types with dysregulated CUL4A expression, such as those with aberrant activation of Wnt signaling.

Public Health Relevance

The research proposal will evaluate how dysregulation of the CUL4A ubiquitin ligase promotes tumorigenesis and tumor resistance to chemotherapy. A better understanding of the roles CUL4 family of proteins play in tumor initiation, maintenance, and chemotherapy resistance will allow for development of improved therapeutic strategies to treat breast cancer, especially the triple negative breast cancer that currently lacks targeted therapeutic modality, as well as other tumor types with dysregulated CUL4A expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA159925-02
Application #
8334017
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Fu, Yali
Project Start
2011-09-16
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$409,503
Indirect Cost
$165,009
Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Jia, Lei; Yan, Fan; Cao, Wenfeng et al. (2017) Dysregulation of CUL4A and CUL4B Ubiquitin Ligases in Lung Cancer. J Biol Chem 292:2966-2978
Yin, Yan; Liu, Liren; Yang, Chenyi et al. (2016) Cell Autonomous and Nonautonomous Function of CUL4B in Mouse Spermatogenesis. J Biol Chem 291:6923-35
Hannah, Jeffrey; Zhou, Pengbo (2015) Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B. Gene 573:33-45
Yang, Chenyi; Boyson, Cynthia A; Di Liberto, Maurizio et al. (2015) CDK4/6 Inhibitor PD 0332991 Sensitizes Acute Myeloid Leukemia to Cytarabine-Mediated Cytotoxicity. Cancer Res 75:1838-45
Kong, F; Zhang, J; Li, Y et al. (2014) Engineering a single ubiquitin ligase for the selective degradation of all activated ErbB receptor tyrosine kinases. Oncogene 33:986-95
Li, Wei; Cooper, Jonathan; Zhou, Lu et al. (2014) Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus. Cancer Cell 26:48-60
D'Alfonso, Timothy M; Hannah, Jeffrey; Chen, Zhengming et al. (2014) Axl receptor tyrosine kinase expression in breast cancer. J Clin Pathol 67:690-6
Zhang, Sufang; Zhao, Hong; Darzynkiewicz, Zbiegniew et al. (2013) A novel function of CRL4(Cdt2): regulation of the subunit structure of DNA polymerase ? in response to DNA damage and during the S phase. J Biol Chem 288:29550-61
Lee, Jennifer; Zhou, Pengbo (2012) Pathogenic Role of the CRL4 Ubiquitin Ligase in Human Disease. Front Oncol 2:21
Liu, Liren; Yin, Yan; Li, Yuewei et al. (2012) Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis. Cell Res 22:1258-69