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A new Twist in the tale of triple-negative breast cancer
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A new study published in the journal Cancer Cell suggests that a nuclear protein known as Twist may point to a potential way forward in treatment of the clinically aggressive triple-negative form of breast cancer. Triple-negative breast cancer is characterised by an activated programme of epithelial-mesenchymal transition (EMT), a process that allows cells to adapt to stressful environments. This is positive when contributing to processes such as embryonic development and wound healing but is unfortunately ‘hijacked’ by tumour cells to facilitate metastasis to secondary sites. It also makes tumour cells resemble stem cells, effectively ‘hiding’ them from therapeutic interventions. Twist is an accelerant of EMT, prompting the interest of researchers in the University of Kentucky Markey Cancer Centre to study it with respect to triple-negative breast cancer.

Triple-negative breast cancer is a particularly unpleasant form of this cancer, featuring high incidence of recurrence and metastasis to sites such as the brain and lung, factors which impact negatively on five year survival statistics. There is a lack of effective therapies for this form of breast cancer, making studies to elucidate its mechanisms even more important.

While Twist was known to be a transcriptional activator of EMT, the mechanism by which Twist exerts this activation was unclear. The Cancer Cell study revealed that Twist acts in an analogous manner to DNA viruses such as papillomaviruses. When these viruses enter the cell, they hijack host cell machinery for their own purposes to allow them to replicate and synthesis their viral DNA and proteins. A favourite target of DNA viruses is a nuclear transcriptional regulator called BRD4. Results of the Cancer Cell study showed that Twist similarly targets BRD4. Twist contains a histone H4-like domain which can bind to a bromodomain of BRD4. This creates a transcription-activating complex (Twist/BRD4/P-TEFb/RNA-Pol II) which targets transcription of the gene WNT5A. This in turn directs production of the protein Wnt-5a, which is implicated in oncogenesis. This process enhanced invasion and stem cell properties of triple-negative cancer cells. Pharmacological inhibition of BRD4 using the known inhibitors JQ1 and MS417 suppressed invasion, stem cell properties and tumourigenicity of these cells. Thus this study identifies a previously unrecognised interaction with BRD4 in directing oncogenic function of Twist in triple-negative breast cancer cells and provides a potential avenue for future drug development to treat this devastating disease. Dr Peter Zhou, the senior author of this paper, concluded that: "This finding has significant clinical ramification, because drugs that can target the Twist-BRD4 interaction provide a new hope for treating life-threatening triple-negative breast cancer."

Sources

University of Kentucky Markey Cancer Center: http://uknow.uky.edu/content/new-uk-stud...st-cancers [Accessed 12 February 2014].

Shi, J. et al, 2014. Disrupting the Interaction of BRD4 with Diacetylated Twist Suppresses Tumorigenesis in Basal-like Breast Cancer. Cancer Cell, 25 (2) 10 February 2014, Pages 210–225
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