Abstract P3-01-18: Kinase D interacting substrate 220 (Kidins220) and disease progression of breast cancer, the role of heat shock protein90 (HSP90)
Authors: Zhao Zhe , Martin Tracey A. , Benedikt Johannes , Cai Shuo , Ye Lin , Davies Eleri , Mansel Robert E , Jiang Wen G. 
Published: March 2020

Background: Kidins220 (Kinase D Interacting Substrate 220) is a transmembrane scaffold protein and was initially found as the substrate of Protein Kinase D. It has several binding partners and plays an important role in neuronal activities and attribute to the occurrence of neuronal disease. Moreover, emerging evidence has revealed the involvement of Kidins220 in regulating cancer development including melanoma, neuroblastoma, and prostate cancer. Our current study investigated the role of Kidins220 in breast cancer and the biological implications on breast cancer cells.

Method: A panel of human breast cancer cell lines were used in the biological studies. Kidin220 Knockdown cell model was established using lentivirus anti-Kidins220 shRNA and the knockdown of Kidins220 was verified in gene and protein levels. Cell matrix attachment and cell migration assay were determined using an automated cell analyser (ECIS). The growth of breast cancer cells was evaluated using colorimetric method. Human breast tumours (n=106) together with adjacent background tissues were collected immediately after surgery. Transcription level of Kidins220 and HSPs in the fresh tissues was determined using quantitative transcript analyses.

Results: In the clinical cohort of breast cancer, an increase in expression of Kidins220 was found in tumour tissues in comparison with adjacent normal tissues. Patients with poor prognosis (NPI&gt;5.4) had the lowest expression of Kidins220 compared with patients with good and moderate prognosis. Likewise, high grade tumours had markedly reduced level of Kidins220. Furthermore, patients remain disease free had the highest Kidins220 level when compared with those who had breast cancer-related incidence. Kaplan-Meier plot showed high level of Kidins220 was linked to longer survival. Our database also revealed that the levels of expression of Kidins200 were significantly correlated with that of HSP90A (Heat Shock Protein-90A) (r=0.37, p&lt;0.001), but not HSP90B. Moreover, breast cancer cells (MDA MB-231 and MCF-7) after losing Kidins220 by way of knockdown showed an increase in cellular migration and cell matrix adhesion, with little changes in cell growth compared with control cells. In these cell based models, HSP90 inhibitor was found to affect Kidins220 mediated changes in matrix adhesion. It was also noteworthy that cells with Kidins220 knockdown had dramatically reduced expression of HSP90, particularly HSP90A.

Conclusion: Kidins220 may act as a tumour suppressor in regulating the disease progression of breast cancer and has a correlation with the survival of patients with breast cancer. Kidins220 regulates the aggressive property including migration and cell matrix attachment of breast cancer with the involvement of HSP90A.

Citation Format: Zhe Zhao, Tracey A. Martin, Johannes Benedikt, Shuo Cai, Lin Ye, Eleri Davies, Robert E Mansel, Wen G. Jiang. Kinase D interacting substrate 220 (Kidins220) and disease progression of breast cancer, the role of heat shock protein90 (HSP90) [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 P3-01-18.