The Science
The caPCNA Story
Three of the founders, Drs. Malkas, Hickey and Hoelz, demonstrated that the DNA Synthesome is altered in malignant cells in that it is mutagenic.
Consequently, during the DNA replication process, a novel cancer-associated isoform of PCNA is expressed, that is caPCNA. This is the product of altered post-translational modifications.
To date, there has been an exact correlation between the observed decrease in DNA synthetic fidelity and the expression of the cancer associated isoform of PCNA (caPCNA) in malignant breast cells and tissue. All data point to caPCNA as having an important role in breast cancer cells. These studies suggest caPCNA presence may be a bona fide hallmark of breast cancer, and as such, must play an important role in these cells. A detailed structure and function analysis of caPCNA in breast cancer cells is likely to lead to important new insights into its role(s) in the cancer cell and disease progression.
The team then created an antibody that specifically recognizes caPCNA. This antibody is the basis for CS-Keys’ current diagnostic platform. This antibody has also been shown to be effective in several other cancer types such as Ovarian, Pancreatic, Esophageal, and Prostate.
>> More about the caPCNA Key Stain
The Synthesome
A characteristic of cancer cells is ongoing DNA damage accumulation, which has also been correlated with disease progression. This observation led to the “Mutator Phenotype Hypothesis”, first coined by Dr. Lawrence Loeb, which stated that faulty, (or error-prone or mutagenic), DNA repair and/or DNA replication led to cancer progression and genomic instability.
- The laboratory of Dr. Linda Malkas was the first to isolate an intact multiprotein DNA synthesis complex (termed DNA synthesome) from a variety of mammalian cell lines and tissues that is both stable and fully functional.
- Subsequent work demonstrated that the synthesome of malignant breast epithelial cells has a significantly decreased DNA synthesis fidelity, (exhibiting a more error-prone synthesis process), than the complex of non-malignant breast epithelial cells.
- It was demonstrated that this occurs in intact breast epithelial cells as well.
These data are the first direct experimental evidence indicating that the DNA synthetic machinery of breast cancer cells is itself, mutagenic. We also showed that non-malignant human breast cell transformation to a malignant state is accompanied by an alteration of a specific protein component of the synthesome, namely proliferating cell nuclear antigen (PCNA). It arises not as a result of genetic mutation, but through a post-translational modification mechanism.