Type

Journal Article

Authors

Stephen Madden
Bryan Hennessy
John Crown
Susan Kennedy
Elaine Kay
Joanna Fay
Aoife Carr
Simon Furney
Malgorzata Milewska
Mattia Cremona
and 3 others

Subjects

Microbiology

Topics
cell line tumor receptor erbb 3 middle aged pharmacogenomic variants docetaxel erbb2 protein human germ line mutation polymorphism single nucleotide carboplatin prognosis biomarkers tumor trastuzumab ubiquitin protein ligases tumor suppressor proteins breast neoplasms bard1 protein human humans disease free survival antineoplastic agents drug therapy receptor erbb 2 erbb3 protein human female therapeutic use support vector machine metabolism genetics

Germline single nucleotide polymorphisms in ERBB3 and BARD1 genes result in a worse relapse free survival response for HER2-positive breast cancer patients treated with adjuvant based docetaxel, carboplatin and trastuzumab (TCH). (2018)

Abstract Breast cancer is the leading cause of cancer related deaths in women worldwide and is classified into subtypes based on the cancer's receptor status. Of these subtypes, those expressing the human epidermal growth factor receptor 2 (HER2) receptor were traditionally associated with poor prognosis. Several advances have been made in the treatment of HER2-positive breast cancer, yet issues of resistance and poor response to therapy remains prevalent. In this study we explored the impact of HER-family and homologous recombination deficiency SNPs on response to patients who received TCH-based (docetaxel (T), carboplatin (C), and trastuzumab (H)) treatment versus those who received other treatment regimens. Using Cox regression analysis, we identified 6 SNPs that correlate with recurrence free survival in our patients and supported our findings using support vector machines. We also used reverse phase protein array analysis to examine the impact ERBB3 SNPs may have on both the PI3K/AKT and MAPK/ERK signaling pathways. Finally, using cell line models, we correlated SNP status with sensitivity to platinum based drugs and docetaxel. We found that patients on a TCH based regimen with the minor allele of the ERBB3 (rs2229046 and rs773123) and BARD1 (rs2070096) SNPs, were significantly more likely to relapse than those women who were not. Additionally, we observed that patients with these ERBB3 SNPs had shown elevated protein expression/phosphorylation of Src kinase, c-MET (Y1234/1235), GSK-3β (S9) and p27, indicating that these SNPs are associated with non-PI3K/AKT signaling. Finally, using cell line models, we demonstrate that the BARD1 SNP (rs2229571) is associated with greater sensitivity to both carboplatin and cisplatin. The BARD1 and ERBB3 SNPs can potentially be used to determine those patients that will have a worse response to TCH based treatment, an effect that may arise from the SNPs impact on altered cellular signaling.
Collections Ireland -> Dublin City University -> PubMed

Full list of authors on original publication

Stephen Madden, Bryan Hennessy, John Crown, Susan Kennedy, Elaine Kay, Joanna Fay, Aoife Carr, Simon Furney, Malgorzata Milewska, Mattia Cremona and 3 others

Experts in our system

1
Stephen F Madden
Dublin City University
Total Publications: 45
 
2
Bryan T Hennessy
Royal College of Surgeons in Ireland
Total Publications: 33
 
3
John Crown
Dublin City University
Total Publications: 104
 
4
Susan Kennedy
Dublin City University
Total Publications: 40
 
5
Elaine W Kay
Royal College of Surgeons in Ireland
Total Publications: 157
 
6
Joanna Fay
Royal College of Surgeons in Ireland
Total Publications: 24
 
7
Aoife Carr
Royal College of Surgeons in Ireland
Total Publications: 8
 
8
Simon Furney
Dublin City University
Total Publications: 3
 
9
Malgorzata Milewska
Royal College of Surgeons in Ireland
Total Publications: 13
 
10
Mattia Cremona
Royal College of Surgeons in Ireland
Total Publications: 11