Poster Presentation 28th Lorne Cancer Conference 2016

TrkA is overexpressed and is a potential adjunct therapeutic target in HER2-positive breast cancers (#143)

Sam Faulkner 1 , Severine Roselli 1 , Christopher Oldmeadow 2 , John Attia 3 4 , John Forbes 3 , Marjorie Walker 3 , Hubert Hondermarck 1
  1. School of Biomedical Sciences & Pharmacy and Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW, Australia
  2. School of Mathematical and Physical Sciences, The University of Newcastle, Callaghan, NSW, Australia
  3. School of Public Health & Medicine, The University of Newcastle, Callaghan, NSW, Australia
  4. Hunter Medical Research Institute, Newcastle, NSW

The neurotrophin tyrosine kinase receptor TrkA (NTRK1) contributes to breast cancer cell invasion and metastasis, but its clinicopathological significance in breast tumours is unclear. In this study, TrkA immunohistochemistry was performed in a cohort of 366 breast tumours including ductal carcinomas in situ (DCIS), invasive ductal carcinomas (IDC), and invasive lobular carcinomas (ILC). TrkA protein was detected in both cancer and myoepithelial cells and was preferentially associated with IDC (39% of cases) as compared to DCIS (24% of cases) (p<0.0001) and ILC (20% of cases) (p<0.0001). There was a linear association between TrkA expression and lymph node invasion (p=0.0052), confirming the involvement of TrkA in the metastatic potential of breast cancer cells. Interestingly, TrkA expression was significantly increased in tumours positive for the human epidermal growth factor receptor-2 (HER2). TrkA was detected in 48% of HER2-positive tumours compared to only 25% of HER2-negative tumours (p<0.0001). When considering molecular subtypes of breast cancer, HER2+ and luminal B tumours were associated with higher TrkA levels (p=0.006). In Western-blotting, TrkA immunoreactivity was observed at 140 kDa and 180 kDa, with higher levels of TrkA in HER2-positive as compared to HER2-negative breast cancer cell lines. In HER2-positive breast cancer cell lines, the pharmacological inhibition of TrkA tyrosine kinase activity resulted in cell growth decrease and was able to potentiate the effect of Trastuzumab. Together, these data reveal the association between TrkA and HER2 protein expression in breast cancer, and suggest that TrkA should be further investigated as a potential adjunct therapeutic target in HER2-positive breast tumours.