The transformation of a non-malignant human breast epithelial cell to a malignant state is accompanied by the alteration of a specific protein, namely proliferating cell nuclear antigen (PCNA). It arises not because of a genetic mutation but through post-translational modification of the protein. To date, there is an exact correlation between an observed decrease in DNA synthesis fidelity and the expression of the cancer specific isoform of PCNA (csPCNA) in malignant breast cells and tissue. We recently developed a novel antibody that specifically detects only the csPCNA isoform, this antibody has enabled us to selectively identify the csPCNA isoform in breast cancer cells and tumor tissues. Overall, our studies suggest the csPCNA isoform uniquely expressed in malignant cells may be a bona fide hallmark of cancer and as such must, therefore, play an important role in the life of cancer cells. This evidence indicates that a thorough structure and function analysis of csPCNA in breast cancer cells may lead to important new insights into its role in cancer cell proliferation and progression. We propose to: (1) identify the post-translational modification(s) responsible for the expression of csPCNA polypeptide in breast cancer cells, (2) determine the role csPCNA plays in the aberrant DNA synthesis fidelity of breast cancer cells, (3) evaluate DNA synthesis fidelity and csPCNA levels during breast cancer progression, (4) determine whether csPCNA displays differential interactions with proteins that have been identified as PCNA binding partners, and (5) validate that the presence of csPCNA in breast tissue is a true indicator of malignancy. Our discovery of csPCNA points to a novel mechanism whereby the alteration of a specific type of post-translational modification may play a key role in abrogating cell cycle check points and contributing to the cascade of events which lead to the accumulation of genetic damage sustained by the cancer cell and ultimately the transformation of the normal cell. Also, the recent development of an antibody that specifically recognizes csPCNA holds the real potential for developing a highly selective reagent that may significantly improve the early detection of malignant breast cells, improve monitoring of remission status, and potentially save thousands of lives each year. In addition, the dissection of its role in reducing DNA synthetic fidelity in malignant cells could suggest potential new targets for therapeutic development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121289-04
Application #
7840432
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Okano, Paul
Project Start
2007-08-09
Project End
2011-05-13
Budget Start
2010-06-01
Budget End
2011-05-13
Support Year
4
Fiscal Year
2010
Total Cost
$287,850
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Smith, Shanna J; Hickey, Robert J; Malkas, Linda H (2016) Validating the disruption of proliferating cell nuclear antigen interactions in the development of targeted cancer therapeutics. Cancer Biol Ther 17:310-9
Smith, Shanna J; Gu, Long; Phipps, Elizabeth A et al. (2015) A Peptide mimicking a region in proliferating cell nuclear antigen specific to key protein interactions is cytotoxic to breast cancer. Mol Pharmacol 87:263-76
Perry, J Jefferson P; Ballard, Gregory D; Albert, Alexandra E et al. (2015) Human C6orf211 encodes Armt1, a protein carboxyl methyltransferase that targets PCNA and is linked to the DNA damage response. Cell Rep 10:1288-96
Gu, Long; Chu, Peiguo; Lingeman, Robert et al. (2015) The Mechanism by Which MYCN Amplification Confers an Enhanced Sensitivity to a PCNA-Derived Cell Permeable Peptide in Neuroblastoma Cells. EBioMedicine 2:1923-31
Lingeman, Robert G; Hickey, Robert J; Malkas, Linda H (2014) Expression of a novel peptide derived from PCNA damages DNA and reverses cisplatin resistance. Cancer Chemother Pharmacol 74:981-93
Gu, Long; Smith, Shanna; Li, Caroline et al. (2014) A PCNA-derived cell permeable peptide selectively inhibits neuroblastoma cell growth. PLoS One 9:e94773
Dai, Heqiao; Hickey, Robert J; Liu, Jianying et al. (2013) Error-promoting DNA synthesis in ovarian cancer cells. Gynecol Oncol 131:198-206
Tan, Zongqing; Wortman, Matthew; Dillehay, Kelsey L et al. (2012) Small-molecule targeting of proliferating cell nuclear antigen chromatin association inhibits tumor cell growth. Mol Pharmacol 81:811-9
Wang, Xiaoyan; Hickey, Robert J; Malkas, Linda H et al. (2011) Elevated expression of cancer-associated proliferating cell nuclear antigen in high-grade prostatic intraepithelial neoplasia and prostate cancer. Prostate 71:748-54
Shen, Fei; Kirmani, Kashif Z; Xiao, Zhimin et al. (2011) Nuclear protein isoforms: implications for cancer diagnosis and therapy. J Cell Biochem 112:756-60

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