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The Receptor Tyrosine Kinase Trka Is Increased and Targetable in HER2-Positive Breast Cancer

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The Receptor Tyrosine Kinase Trka Is Increased and Targetable in HER2-Positive Breast Cancer biomolecules Article The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer Nathan Griffin 1,2, Mark Marsland 1,2, Severine Roselli 1,2, Christopher Oldmeadow 2,3, 2,4 2,4 1,2, , 1,2, John Attia , Marjorie M. Walker , Hubert Hondermarck * y and Sam Faulkner y 1 School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; nathan.griffi[email protected] (N.G.); [email protected] (M.M.); [email protected] (S.R.); [email protected] (S.F.) 2 Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, NSW 2305, Australia; [email protected] (C.O.); [email protected] (J.A.); [email protected] (M.M.W.) 3 School of Mathematical and Physical Sciences, Faculty of Science and Information Technology, University of Newcastle, Callaghan, NSW 2308, Australia 4 School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia * Correspondence: [email protected]; Tel.: +61-2492-18830; Fax: +61-2492-16903 Contributed equally to the study. y Received: 19 August 2020; Accepted: 15 September 2020; Published: 17 September 2020 Abstract: The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (p < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (p = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours. Keywords: breast cancer; tyrosine kinase receptor A (NTRK1/TrkA); human epidermal growth factor receptor 2 (HER2); clinical biomarker; therapeutic target 1. Introduction Targeted therapies against the human epidermal growth factor receptor-2 (HER2) have demonstrated their clinical efficacy in breast cancer. However, approximately 50% of HER2 overexpressing breast tumours are refractory to current anti-HER2 approaches [1]. HER2 positivity represents 15–20% of all breast cancers and is defined by protein expression, HER2 gene copy number alterations or by the ratio of HER2/CEP17 [2,3]. Unfortunately, there are no clinically validated predictive biomarkers and the use of anti-HER2 agents is still determined based on the HER2 status of Biomolecules 2020, 10, 1329; doi:10.3390/biom10091329 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, 1329 2 of 13 the primary tumour. However, a key oversight in current diagnostic and prognostic methodologies is that HER2 status of the primary tumour may vary compared to metastases in approximately 25% of all cases [4,5]. This further highlights the crucial need to identify biomarkers of resistance and metastatic progression as well as adjunct therapeutic targets for improving the management of HER2-positive breast cancer [2,6]. The tyrosine kinase receptor TrkA (or neurotrophin receptor kinase 1, NTRK1) has been predominately studied for its role during the development of the nervous system. In developing neurons, TrkA activation upon binding of its ligands nerve growth factor (NGF) or neurotrophin-3 (NT-3) results in the stimulation of various tyrosine kinase-induced signaling pathways leading to neuronal outgrowth [7]. In the adult, where neurogenesis is largely reduced, TrkA acts as a pain receptor in sensory neurons and contributes to the transmission of pain signals to the central nervous system [8]. Interestingly, TrkA is also oncogenic and there is accumulating evidence for its overexpression and involvement in cancer progression [9–14], including in the form of TrkA fusion proteins as described in lung cancer [15]. Furthermore, TrkA is a therapeutic target in oncology and Trk inhibitors are being tested in several clinical trials [16–19]. In breast cancer, TrkA has been shown to stimulate tumour cell invasion and metastasis through the activation of ERK, PI3K, SRC and AKT signaling pathways [10,20–22]. TrkA (NTRK1) gene overexpression has also been shown to occur preferentially in invasive tumours [23]. In breast cancer patients, increased TrkA phosphorylation has been described in malignant pleural effusions [24] while phosphorylation of Tyr674/675 and activation of tyrosine kinase activity in the cytoplasmic domain of TrkA has been shown as a potential prognostic biomarker [25]. However, TrkA protein expression in a large clinically relevant cohort of breast tumours, as well as its overall clinical significance remain unclear [26]. The present study aimed to elucidate the immunohistochemical profile and clinical ramifications of TrkA expression in a large and pathologically diverse cohort of breast cancers. We report a significantly higher protein expression of TrkA in invasive ductal carcinomas (IDC) as compared with invasive lobular carcinomas (ILC) and ductal carcinomas in situ (DCIS). Interestingly, TrkA protein expression was also associated with HER2 status. Furthermore, in vitro experiments using a panel of breast cancer cell lines confirmed an overexpression of TrkA and phospho-TrkA in HER2-positive cell lines and demonstrated that targeting phospho-TrkA signaling, using the Trk inhibitor GNF-5837, resulted in decreased cell viability. Overall, these data suggest a potential utility of TrkA as an additional therapeutic target in HER2-positive breast cancers. 2. Materials and Methods 2.1. Breast Tissue Samples High-density tissue microarrays (TMA, catalogue numbers; BR1921, BR1921a and BR8011) were obtained from US Biomax Inc. (Rockville, MD, USA) which included 316 cases of invasive breast carcinomas (158 IDC and 158 ILC) and 50 cases of non-invasive DCIS. The following clinicopathologic information was available for analysis: patient age, histopathological diagnosis, classification of malignant tumours (TNM), stage and grade. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status was also provided. US Biomax Inc. quality controls are described as follows. Each single tissue spot on every array slide is individually examined by pathologists certified according to WHO published standardizations of diagnosis, classification and pathological grade. Each specimen collected was consented to by both hospital and individual. Discrete legal consent was obtained and the rights to hold research uses for any purpose or further commercialized uses were waived. This study was conducted in accordance with the Declaration of Helsinki, and the protocol approved by the Human Research Ethics Committee of the University of Newcastle, Australia (HREC reference: H-2012-0063). Biomolecules 2020, 10, 1329 3 of 13 2.2. Immunohistochemistry and Quantification of TrkA Expression Immunohistochemistry was performed as previously described by our laboratory [27]. A TrkA antibody (1:200 dilution; catalogue number 2508, Cell Signaling Technology, Danvers, MA, USA) was applied to all TMAs. TMAs were digitized using the Aperio AT2 scanner (Leica Biosystems, Victoria, Australia) at 400 absolute resolution. Two independent observers (S.F. and N.G.) and × an experienced pathologist (M.M.W.) quantified the intensity of TrkA staining as 0 (no staining), 1 (weak staining), 2 (moderate staining) and 3 (strong staining), as described previously [27,28]. Negative control testing was also performed using a rabbit (DA1E) monoclonal antibody IgG Isotype Control (0.8 µg/mL; catalogue number 3900, Cell Signaling Technology) and is shown in Supplementary Figure S1. Clinicopathologic parameters were compared with TrkA staining intensity and analysed as ordinal variables using chi-squared (χ2) or Fisher’s exact tests. To test for statistically significant associations, we developed log-linear models to adjust for the bivariate associations for other potential confounders, which provided an additional chi-squared (χ2) test adjusted for all other variables; these included carcinoma type (IDC vs. ILC vs. DCIS), lymph node invasion (yes/no), ER+ (yes/no), PR+ (yes/no) and HER2+ (yes/no). Analyses were based on complete cases and performed using Stata (version 14.1, Statacorp, College Station, TX USA), with additional figures created using Prism (version 8.2.0, GraphPad Software, San Diego, CA, USA). 2.3. Cell Culture Breast cancer cell lines MDA-MB-231 (catalogue number HTB-26), MCF-7 (catalogue number HTB-22), BT-474 (catalogue number HTB-20) and SK-BR-3 (catalogue number HTB-30) were purchased
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