Scientists at the Fred Hutchinson Cancer Research Center found that mice lacking one copy of a gene called CTCF have abnormal DNA methylation and are markedly predisposed to cancer. This ground-breaking research helps solve a mystery that has loomed for over 30 years – which gene or genes cause the frequent loss of one copy of chromosome 16 in breast cancer cells.
Dr. Gala Flippova, staff scientist at Fred Hutchinson, and his colleagues originally cloned the CTCF gene and mapped it to chromosome 16, within the same region that is frequently lost in human cancers. Though CTCF is a very well-studied protein and influential in gene expression, it had not been linked to breast cancer. Many ruled out CTCF as a candidate breast cancer gene on chromosome 16 simply because it did not conform to the predominant “two-hit” model, even though a study co-authored by Dr. Chris Kemp at Fred Hutch had demonstrated that the loss of only one – not two – copies of the tumor suppressor gene was enough.
In the current study, Dr. Kemp and his team of researchers investigated whether “loss of just one copy of the CTCF gene could trigger epigenetic changes and predispose to tumor development.” They found what they predicted – the loss of one copy of CTCF caused large scale epigenetic changes and greatly enhanced tumor formation in multiple tissues. A recent large scale analysis of the human cancer genome also revealed that deletions or mutations in CTCF are one of the most common events in breast, endometrial, and other human cancers.
Combined with previous research, this new study illustrates that CTCF is a major tumor suppressor gene in human cancer and highlights the successful use of mouse models to determine if a candidate gene has a function in cancer. These findings lend insight into the origins of DNA methylation alterations in cancer, suggesting that epigenetic instability may both precede and accelerate the evolution of cancer.
“This answers a 30 year riddle in cancer research,” said Dr. Kemp. “And it shows once again, as we first showed in 1998, that one hit is enough.”
Source: Learn all about it and read more about their findings here: CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer. Kemp, Christopher J. et al.
References: A 30-year puzzle in breast cancer is solved. Fred Hutchinson Cancer Research Center. 2014.