To determine how polymorphisms in the stress hormone receptor ADRB2 affect treatments in patients with Triple Negative Breast Cancer

Description

Adrenaline and noradrenaline are hormones that are released in the body under stressful conditions. They bind to receptors on the surface of cells called adrenergic beta-2 receptors (ADRB2), switching the receptor on and producing changes within the cell. We have shown that when these hormones bind ADRB2 receptors on the surface of cancer cells, they stop some cancer treatments (chemotherapy) from working.

Our team has recently shown that a common type of genetic variation in the gene that codes for the ADRB2 receptor can increase the risk of cancer recurrence and death in women with breast cancer treated with chemotherapy.

This risk may be because the genetic variation changes how the receptor responds to stress hormones such as adrenaline and noradrenaline, potentially reducing the effects of chemotherapy.

We are now going to validate our findings by analysing more patient samples to determine whether we can predict patients’ outcome based on the genetic variant. We also aim to use a technique known as gene editing to introduce the genetic variant into cells that can be grown in the laboratory.

This will enable us to investigate whether drugs could be used to counteract the harmful effects of the variant, thereby supporting clinicians in predicting how well a patient will respond to chemotherapy and improving patient prognosis.

Key findings

In our recent Team Verrico funded project where we sourced 60 formalin fixed paraffin embedded (FFPE) TNBC tumours from the Breast Cancer Now Tissue Bank (BCN-TB) and 60 from the Welsh Cancer Bank, we sought to determine SNP haplotype frequencies in codons 16 and 27 of ADRB2, and any association with cancer recurrence and death.

For each patient we requested information regarding date of diagnosis, recurrence, survival status, date of death (if death had occurred) and whether death had been cancer related. DNA successfully extracted from tissue was sequenced to determine individual haplotypes and immunohistochemistry was used to demonstrate ADRB2 receptor expression. 

We found that the G-G haplotype was most common with 28% of patients harbouring these SNP alleles. A-C was present in 24% of patients, G-C in 6% and we did not observe the A-G haplotype in any of the patients. There was no association between a single codon (16 or 27) and recurrence or death, however, there was a significant association between the G-C haplotype and recurrence, p<0.05 and there was a trend towards an association with death, P= 0.06. The strong linkage disequilibrium [9] of the ADRB2 codon 16 and 27 indicate that these findings have the potential to be clinically relevant. All haplotypes expressed the ADRB2 receptor as shown by immunohistochemistry (Figure 2a, b).
StatusActive
Effective start/end date1/06/1831/07/19

Keywords

  • Triple Negative Breast Cancer