Research efforts in the laboratory of
McGowan Institute for Regenerative Medicine
affiliated faculty member Jean Latimer, PhD (pictured), assistant professor at the University of Pittsburgh in the Department of Obstetrics, Gynecology and Women’s Health and also a faculty member in the Cellular and Molecular Pathology Graduate Training Program and the University of Pittsburgh Cancer Institute, focus on DNA repair deficiencies as a causative factor in breast carcinogenesis. Dr. Latimer's laboratory has developed a multiple-lineage tissue engineering system for primary culture of Human Mammary Epithelial Cells. Dr. Latimer has also used this methodology to culture breast tumors as well as non-diseased tissue with a success rate of 85%. In these studies her laboratory measured DNA repair capacity as an etiological factor in breast tumorigenesis.
Dr. Latimer’s most recent paper entitled “Nucleotide excision repair deficiency is intrinsic in sporadic stage I breast cancer” will appear in an upcoming edition of the Proceedings of the National Academy of Sciences of the USA. In this paper, she writes:
The molecular etiology of breast cancer has proven to be remarkably complex. Most individual oncogenes are disregulated in only about 30% of breast tumors, indicating that either very few molecular alterations are common to the majority of breast cancers, or they have not yet been identified. In striking contrast, we now show that 19/19 stage I breast tumors tested with the functional unscheduled DNA synthesis (UDS) assay exhibited a significant deficiency of DNA nucleotide excision repair (NER) capacity relative to normal epithelial tissue from disease-free controls (N = 23). Loss of DNA repair capacity, including the complex, damage-comprehensive NER pathway, results in genomic instability, a hallmark of carcinogenesis.
By microarray analysis, mRNA expression levels for 20 canonical NER genes were reduced in representative tumor samples vs. normal. Significant reductions were observed in 19 of these genes analyzed by the more sensitive method of RNAse protection. These results were confirmed at the protein level for 5 NER gene products.
Taken together, these data suggest that NER deficiency may play an important role in the etiology of sporadic breast cancer, and that early stage breast cancer may be intrinsically susceptible to genotoxic chemotherapeutic agents, such as cis-platinum, whose damage is remediated by NER. In addition, reduced NER capacity, or reduced expression of NER genes, could provide a basis for the development of biomarkers for the identification of tumorigenic breast epithelium.
Bio: Dr. Jean Latimer
Abstract (Proceedings of the National Academy of the Sciences of the USA. Published online before print November 30, 2010)