Abstract P5-10-01: Cellular senescence within HER2-amplified breast cancer: Potential implications for breast cancer immune surveillance and HER2-targeted therapy resistance

Abstract

Abstract Background:Oncogene-induced senescence is considered as a barrier to tumor progression that arrests cells at risk for malignant transformation. Nevertheless, numerous findings demonstrate that senescent cells may also have the opposite function and promote tumor progression through the release of multiple factors called the senescence-associated secretory phenotype or senescence secretome. It is likely that the composition and the physiological consequences mediated by the senescence secretome are dependent on the oncogenes that trigger the senescence program. Breast cancer represents a heterogenous disease that can be divided into breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities. Therefore, tumor initiation and progression of breast cancer subtypes is triggered by variable oncogenic stimuli, and differences in the senescence secretomes within breast tumors might be responsible for tumor initiation, progression, metastasis and therapeutic response. Beside many studies concerning the role of senescence as a barrier to tumor progression using murine xenograft models very few investigations have been performed to elucidate how often senescent tumor cells appear within untreated human tumors, and if present whether these senescent tumor cells may play a role in disease progression, cancer immunosurveillance and therapy resistance. Methode: In the present study we analysed the appearance of senescent cells within invasive human breast cancers from 129 untreated patients. Cellular senescence was detected by the use of SAβ-gal staining and by immunohistochemical detection of p16, p21, p53, Ki67 and lamin B1. Results: Detection of cellular senescence by the use of SAβ-gal staining and detection of p16, p53, Ki67 and lamin B1 within invasive breast carcinomas indicate that senescent tumor cells varies strongly according to the breast cancer subtype. The highest percentages of senescent tumor cells exist within in the HER2-positive and luminal A breast carcinomas whereas no or very few senescent tumor cells were found in triple negative breast tumors. Based on these findings we suggest that the composition of secretomes released by senescent tumor cells from different breast cancer subtypes might be very distinct in respect to their ability to recruit immune cells, which can eliminate senescent tumor cells on one hand and regulate tumor growth, immune surveillance and therapy resistance on the other. Conclusion: Further characterization of senescent secretomes from HER2 and other breast cancer subtypes and their potential role in tumor progression, immune surveillance and therapy response might be warranted for the understanding of cancer biology as well as prognostic and therapeutic applications. Citation Format: Thaler S, Schad A, Kirkpatrick CJ, Sleeman JP, Springer E, Schmidt M, Cotarelo CL. Cellular senescence within HER2-amplified breast cancer: Potential implications for breast cancer immune surveillance and HER2-targeted therapy resistance [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-10-01.