The absence of Brm exacerbates photocarcinogenesis

Abstract

Brm is an ATPase subunit of the SWI/SNF chromatin-remodelling complex. Previously, we identified a novel hotspot mutation in Brm in human skin cancer, which is caused by exposure to ultraviolet radiation (UVR). As SWI/SNF is involved in DNA repair, we investigated whether Brm-/- mice had enhanced photocarcinogenesis. P53+/- and Brm-/-p53+/- mice were also examined as the p53 tumor suppressor gene is mutated early during human skin carcinogenesis. Mice were exposed to a low-dose irradiation protocol that caused few skin tumors in wild-type mice. Brm-/- mice with both p53 alleles intact had an increased incidence of skin and ocular tumors compared to Brm+/+p53+/+ controls. Brm loss in p53+/- mice did not further enhance skin or ocular cancer incidence beyond the increased photocarcinogenesis in p53+/- mice. However, the skin tumors that arose early in Brm-/- p53+/- mice had a higher growth rate. Brm-/- did not prevent UVR-induced apoptotic sunburn cell formation, which is a protective response. Unexpectedly, Brm-/- inhibited UVR-induced immunosuppression, which would be predicted to reduce rather than enhance photocarcinogenesis. In conclusion, the absence of Brm increased skin and ocular photocarcinogenesis. Even when one allele of p53 is lost, Brm has additional tumor suppressing capability.

SWI/SNF-Mediated Lineage Determination in Mesenchymal Stem Cells Confers Resistance to Osteoporosis

“…BRM is epigenetically silenced in a wide range of tumors 30, 31, and BRM‐null mice are sensitive to carcinogen‐induced tumors 41, 42, but the mice do not show increased spontaneous susceptibility to cancer 6, 30, 31, and BRM has actually been identified as a target for cancer treatment, discussed further below. Developmental changes linked with BRM insufficiency are surprisingly few.…”

Brm Inhibits the Proliferative Response of Keratinocytes and Corneal Epithelial Cells to Ultraviolet Radiation-Induced Damage

“…Brm −/− and Trp53 +/− mice were on a C57BL/6 background and were bred and housed at the University of Sydney animal house [7]. This study was carried out in strict accordance with the recommendations in the Australian code of practice for the care and use of animals for scientific purposes by the National Health and Medical Research Council of Australia.…”

“…In addition, BRM protein was reduced by approximately 10-fold in 100% of the human SCC and BCC that we examined [6]. Functional evidence that Brm is a tumour suppressor gene for skin and ocular cancer came from our photocarcinogenesis studies in Brm −/− mice [7]. Brm −/− mice had enhanced skin and ocular cancer formation compared to wild type ( Brm +/+) controls when exposed to ultraviolet radiation (UV).…”

“…Hence we also examined the effect of Brm loss on photocarcinogenesis in mice with loss of a Trp53 allele. Even with this underlying loss of p53 function, Brm loss increased the growth rate of early appearing skin cancers [7].…”

Lichtbedingte Schädigungen: Vorboten von aktinischer Keratose und frühem Plattenepithelkarzinom

“…Die Untersuchung der BRM-und BRG-1-Proteine hat den Verlust der beiden Proteine beim SCC, nicht aber bei AK ergeben, was darauf hindeutet, dass Mutationen in diesem Gen erst in einem späteren Stadium der Progression von AK zum SCC auftreten [9]. Untersuchungen an gentechnisch veränderten Mäusen haben bestätigt, dass die Depletion von BRM den Schutz der Haut vor Photokarzinogenese abschwächt [10]. Somit weisen Daten sowohl aus Human-als auch aus Tierstudien darauf hin, dass Mutationen von BRM eine wichtige Rolle in den späteren Stadien der Progression von AK zum SCC spielen und möglicherweise durch UV-Strahlung induziert werden.…”