F_No_faking_landscape

No FAKing it... A real new development in the battle against breast cancer

By Hannah Mackay
MRC Toxicology Unit, Leicester, UK

This summary was highly commended by the judges for Access to Understanding 2015

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In the UK, breast cancer is the most common form of cancer and is third highest in terms of the number of deaths caused per year1. It therefore presents a severe problem and discovery of new biomarkers to improve diagnosis and treatment is critically needed. One biomarker being tested is a protein known as FAK (Focal Adhesion Kinase) and it could have significant implications for breast cancer patients.

Breast cancer – why it needs our attention

One major obstacle faced with breast cancer is that it is an extremely diverse disease. Gene analyses have only fairly recently allowed classification of four main sub-types: luminal A, luminal B, Her2 and basal-Like (BL). The genetic differences result in variances in cellular proteins and therefore also disease characteristics and severity. For example, BL breast cancer is particularly aggressive and lacks the proteins present in other sub-types, it is therefore also known as ‘Triple Negative’ (TN) breast cancer. These missing proteins are usual targets for treatment options, highlighting an unquestionable need for new specific therapies for BL breast cancer. Better understanding of each sub-type is an issue that needs to be urgently addressed.

What is FAK and why is it so important?

FAK is a protein, known as a tyrosine kinase, which regulates the movement, proliferation and survival of cells. Furthermore, cells with too much FAK have been linked with advanced cancers and in particular the formation of blood vessels that allow tumour growth. Colon, breast, lung and cervical cancer cells have all been shown to have high levels of the FAK protein. FAK has also been shown to be abundant in the tissues surrounding the tumour; of particular interest are the endothelial cells that line the blood vessels supplying the tumour. Mice studies demonstrated that inhibition of endothelial FAK levels correlated with decreased tumour growth via the disruption of the blood supply to the cancerous tissue.

Given this correlation between FAK abundance and cancer, FAK inhibitors are now being explored as a potential cancer treatment. Small molecule inhibitors that bind to FAK and alter the central activity domain in the protein have now reached clinical trials stage². Despite this progress and the mouse models linking between endothelial FAK and cancer, there have been no investigations exploring the relationship between endothelial cell FAK levels and breast cancer sub-types or disease severity. Until now.

What the researchers did, and what they discovered

The London research team collected sections of breast cancer tissue from 149 patients, all suffering from invasive breast cancer. The particular sub-type, along with other patient details such as age, gender and disease progression were collated. A series of fluorescent staining techniques were performed on the samples, whereby the FAK protein levels could be identified. From this, statistical analysis allowed FAK levels to be measured and compared with important characteristics including breast cancer sub-type, disease progression and severity.

Endothelial and cancer cell FAK levels were high in luminal B sub-types and low in luminal A sub-types. However, the relationship between luminal A and low endothelial FAK levels was more substantial and significant than with low cancer cell FAK levels. This is an important finding as endothelial FAK levels have never before been associated with breast cancer sub-type and could therefore help clinicians to diagnose this sub-type. While the patient group sizes for Her2 and luminal B sub-types were likely too low to draw conclusions, interestingly, regardless of sub-type, the more aggressive tumours had higher FAK levels. Breast cancer grading varies from 1-3, with increasing severity, and grade 3 tumours were directly related to excessive FAK levels. Grade 3 carries a worse prognosis for the patient and so using FAK levels as an indicator could aid diagnosis, allowing treatment plans for these more severe cancers that are at this time notoriously difficult to manage.

Why this is important and what’s next?

Uncovering associations between endothelial FAK levels and severe breast cancer offers great promise for future diagnosis and treatment. The difference in endothelial FAK levels between sub-types suggests that non-luminal A sub-types are most likely to respond to FAK inhibitors. The relationship between FAK and high grade tumours indicates FAK may even play a role in the development of these aggressive cancers; a vastly important finding. In addition, the fact that endothelial FAK levels are found to be high offers another big benefit as blood vessel cells are easier to target with drugs than cancer cells. Future work should include more patient samples, compare endothelial FAK levels with survival rates and look at the use of endothelial FAK as a biomarker for clinical trials. This study is the first of its kind to link endothelial FAK levels with breast cancer, but it is likely it will not be the last.

References

1 http://www.cancerresearchuk.org/cancer-info/cancerstats/keyfacts/

2 http://EuropePMC.org/abstract/MED/25380750

This article describes the research published in:

Tumour-associated endothelial-FAK correlated with molecular sub-type and prognostic factors in invasive breast cancer
A. N. Alexopoulou, C. M. Ho-Yen, V. Papalazarou, G. Elia, J. L. Jones, K. Hodivala-Dilke BMC Cancer (2014) 14, 237
http://EuropePMC.org/articles/PMC3997837

This article was selected for inclusion in the competition by Cancer Research UK.

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