Background: Kidins220 (Kinase D Interacting Substrate 220) also known as ARMS (ankyrin repeat-rich membrane spanning) is a transmembrane protein that plays a significant role in neuronal development. It acts as the common downstream effector of neuronal signalling regulated by neurotrophin family including nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). Expression abnormalities of Kidins220 have been identified in certain solid tumours, but the role played remains controversial. The present study aimed to examine the correlation between Kidins220 and BDNF, factor known to be aberrantly expressed in breast cancer cells (1,2), together with NGF and NGF receptor (BGFR). The involvement of Kidins220 in the chain event of cells response to BDNF, in particular the role played by phospholipase-gamma (PLC- γ) were also been determined.
Method: Human breast cancer tissues were collected immediately after surgery. The transcription levels of Kidins220 and the neurotrophic factors and their receptors were determined using quantitative transcript analyses. The correlations between Kidins220 with BDNF, NGF, and NGFR were analysed against the clinical and pathological parameters in the clinical breast cancer cohort. Kidins220 knockdown cell models, using MDA MB-231 and MCF-7 cells, were created by employing anti-Kidins220 shRNA lentiviral technologies. Cell matrix attachment, cellular migration and cell growth were determined in breast cancer cells treated with BDNF and PLC- γ specific inhibitors and analysed using an automated cell analyser (ECIS) and crystal violet method, respectively.
Result: The analyses of the clinical cohort demonstrated reduced expression of NGF and NGFR in high grade and node positive breast tumours, which is in contrast to the the reported pattern seen with BDNF expression. Furthermore, the expressions of NGF and NGFR were reduced in patients with poor prognosis and clinical outcomes. Interestingly, Kidins220 was found to have a significant negative correlation with BDNF (r=-0.429, p<0.001), but positive correlation with NGF (r=0.269, p<0.01) and NGFR (r=0.211, p<0.01). Knockdown of Kidins220 increased cellular migration in MDA-MB-231 and MCF-7 breast cells. In vitro, breast cancer cells responded to BDNF and exhibited changes in cellular migration, after knocking down Kidins220 in the cells. Loss of Kidins220 also resulted in cells which were more responsive to BDNF treatment when compared with the controls. Moreover, breast cancer cells exhibited a marked response to PLC-γ inhibitor, in the presence of BDNF, this was particularly so when they lost Kidins220.
Conclusion: Our observations suggest that Kidins220 is involved in the metastasis of breast cancer, and it is a potential regulator in the response chain to neurotrophic factors including BDNF. Furthermore, it down-regulates the cells in response to BDNF, which is connected to PLC-γ.
1. Patani N et al. Brain-derived neurotrophic factor expression predicts adverse pathological & clinical outcomes in human breast cancer.Cancer Cell Int. 2011, 11:23
2. Yang X et al. Biological influence of brain-derived neurotrophic factor on breast cancer cells. Int J Oncol. 2012, 41:1541
Citation Format: Zhe Zhao, Tracey A. Martin, Johannes Benedikt, Shuo Cai, Lin Ye, Kefah Mokbel, Eleri Davies, Robert E. Mansel, Wen G. Jiang. Kidins220 (kinase D interacting substrate 220) has a connection with neutrotrophic related factors, BDNF and NGF, in human breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-07-01.