Scientists Discover ZNF703, a Breast Cancer 'oncogene'

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Cancer researcher scientists, based at Cancer Research UK’s Cambridge Research Institute at the University of Cambridge and at the British Columbia Cancer Agency in Vancouver, Canada, have identified a gene that, when overactive, triggers a particularly aggressive form of breast cancer to develop.

This gene, ZNF703, is the first new breast cancer ‘oncogene’ discovered in over five years. An oncogene is a cancer-causing gene that when overactive upset the normal checks and balances that control when and how often a cell divides.

The research was published in the journal EMBO Molecular Medicine this past week alongside a study from an independent research group identifying the same gene, providing definitive evidence that ZNF703 is a genuine breast cancer oncogene.

To make the discovery the researchers used ‘microarray technology’ which allows large numbers of tissue samples to be tested simultaneously, picking up subtle differences in gene activity between normal cells and cancer cells.

The researchers had already identified a region on human chromosome eight likely to harbor genes linked to the development of a more aggressive form of estrogen positive breast cancer, because multiple copies of it are commonly found in tumors but not in healthy tissue.

Focusing on this region, they studied the patterns of gene activity in 1172 breast tumors, as well as breast cancer cells grown in the lab. This allowed them to eliminate one gene at a time until there was only one gene left within that region that was overactive in all the samples tested.

Crucially there were two patients in which ZNF703 was the only gene shown to be overactive, providing further evidence that it was the driving force in the development of the cancer.

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It is thought that testing patients tumors to see if the gene - called ‘ZNF703’ - is overactive could help identify patients with more aggressive tumors, so their treatment can be tailored accordingly, similar to the way testing for the oncogene Her2 helps determine who will respond to Herceptin.

Dr Lesley Walker, director of cancer information at Cancer Research UK, said: “This is the first gene of its kind to be discovered in breast cancer for five years. This is exciting because it’s a prime candidate for the development of new breast cancer drugs designed specifically to target tumors in which this gene is overactive. Hopefully this will lead to more effective cancer treatments in the future.”

The second group specifically studied Luminal B breast cancers which represent a fraction of ER-positive tumors associated with poor recurrence-free and disease-specific survivals in all adjuvant systemic treatment categories including hormone therapy alone.

Using mass spectrometry, they identified ZNF703 as a cofactor of a nuclear complex comprising DCAF7, PHB2, and NCOR2. ZNF703 expression results in the activation of stem-cell related genes expression leading to an increase in cancer stem cells.

They were able to show that ZNF703 is implicated in the regulation of estrogen receptor and E2F1 transcription factor which points to the prominent role of ZNF703 in transcription modulation, stem cell regulation and luminal B oncogenesis.

Sources
ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium; Carroll JS, Curtis C, Aparicio S, Caldas C, et al; EMBO Molecular Medicine, Article first published online: 18 FEB 2011; DOI: 10.1002/emmm.201100122

ZNF703 gene amplification at 8p12 specifies luminal B breast cancer; Sircoulomb F, Nicolas N, et al; EMBO Molecular Medicine, Article first published online: 18 FEB 2011; DOI: 10.1002/emmm.201000121

Cancer Research UK Press Release, February 18, 2011

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