Role for PTEN in DNA Damage Removal and Prevention of Non-Melanoma Skin Cancer

Using in vitro techniques and mouse models, scientists at the University of Chicago Department of Medicine and colleagues have demonstrated that downregulation of PTEN in epidermal keratinocytes predisposes skin to ultraviolet B (UVB)-induced tumorigenesis. PTEN was first identified in 1997 and is known to prevent genomic instability and promote cellular repair preventing neoplastic growth and tumor progression.

The findings support the essential role of PTEN in skin tumor supporesion via its function in the removal of DNA damage caused by UVB radiation. The research paper was published on July 26, 2011 in Cancer Research (doi: 10.1158/0008-5472.CAN-10-4614)). 

Skin cancer is the most common type of cancer in the United States, with non-melanoma cancer accounting for 96% of all skin malignancies. More than 1 million new cases of skin cancer are diagnosed each year. These patients account for 40% of annual newly diagnosed cancers. This number is continuosly rising due to both more cases as well as more public awareness, which increases the number of diagnoses. The biggest skin cancer risk factor is UVB radiation from sunlight. 

Yu-Ying He, Ph.D., an assistant professor of medicine at the University of Chicago, along with colleagues at other institutions, created mice with only one copy of the PTEN gene and found that the reduced levels of PTEN resulted in a higher probability of the mice developing UVB-induced skin cancers. 

“This was an unexpected finding and definitely provides a new approach for chemoprevention strategies,” she said. “It’s possible that if we can increase PTEN activity through nutritional supplements or some sort of pharmaceutical intervention, we may be able to prevent this common cancer, stated professor He. 

To demonstrate the role of PTEN in the development of human skin cancers, the researchers analyzed skin samples from normal, premalignant lesions as well as invasive squamous cell
carcinoma (SCC) samples. PTEN levels were found to be reduced in 92% of premalignant lesions (23 of 25) and 94% of invasive SCC lesions (26 of 28) compared to normal skin samples (0 of 16). 

The study also demonstrated that PTEN is essential for repair of UVB-induced DNA damage in human keratinocytes and that its downregulation delayed exit from growth arrest after irradiation.
The experiments show that PTEN positively regulates global genomic nucleotide excision repair in keratinocytes. When the skin cells were exposed to UVB radiation, the cells that had lower PTEN levels had slower DNA repair because of the loss of a key DNA repair protein, xeroderma pigmentosum C (XPC). When the researchers restored the levels of XPC, DNA repair was also partly restored. 

“Cells without appropriate levels of PTEN were not able to repair sufficiently,” said He. Professor He’s laboratory plans to evaluate thechemopreventive potential of restoring PTEN function as a follow-up to these results.