loss of a single (of two copies) of a tumor suppressor gene enough to flip bc "switch

[Lani]

Tumor suppressor tips the balance in breast cancer development

MedWire News: Loss of the tumor suppressor gene Tip60 is associated with the development of aggressive breast tumors, a discovery that could have important implications for how certain breast cancers are treated in the future, reveals an international team of researchers.

"We suggest that this is because critical levels of Tip60 are required for mounting an oncogene-induced DNA-damage response (DDR) in incipient tumor cells, the failure of which might synergize with p53 mutation towards tumor progression," the researchers explain

Chiara Gorrini (European Institute of Oncology, Milan, Italy) and colleagues found that Tip60 messenger (m)RNA levels were significantly reduced in 21 of 52 ductal breast carcinomas and 17 of 20 high-grade tumors, relative to matched normal tissue.

The researchers also measured TIP60 protein in an additional 179 breast cancers using immunohistochemistry on tissue microarrays. In 129 (72%) cases there was no TIP60 protein in the cell nucleus, whereas in normal breast tissue most of the protein was localized in the cell nucleus.

The proportion of cancers lacking nuclear TIP60 protein was even higher in aggressive cancers, with over 70% of grade 2, and over 90% of grade 3 tumors negative for TIP60.

Reporting their findings in the journal Nature, the researchers suggest that defects in the Tip60 gene appear at an early stage of breast cancer development and predispose women to aggressive tumors.

Co-author Tim Crook (Breakthrough Breast Cancer Research Centre, London, UK) commented: "The identification of Tip60's role in breast cancer is a step towards predicting the aggressiveness of the disease and then individualizing chemotherapy for women."

He added: "If we can transfer this knowledge to the clinic, it could have dramatic effects."

The study also found that, unlike most tumor suppressors, the Tip60 gene only needs to have one copy altered to stop functioning properly. The researchers suggest that critical levels of TIP60 are required for it to perform its vital role in DDR in incipient tumor cells.

Antonia Dean, a Clinical Nurse Specialist from the UK charity Breast Cancer Care, emphasized the need for further studies to fully determine how these findings can be translated into practical benefits for people with breast cancer.



Nature 2007; 488: 1063-1067

http://www.nature.com/nature/journal...ture06055.html