Abstract 2849: Shc1 as a potential metastasis driver gene of breast cancer

Abstract

In the US, women diagnosed with non-metastatic breast cancer have a 5-year survival rate of approximately 98.8%. However, if women develop metastases the survival rate drops to 27.4%, highlighting the need for a better understanding of the mechanisms that regulate and drive metastasis. Somatically acquired mutations that drive metastasis were originally hypothesized by Nowell in the 1970s; however, to date few candidate metastasis driver mutations have been identified and the role of these mutations in metastasis are not well-understood. Using the PyMT genetically engineered mouse model of luminal metastatic breast cancer, previous work by our group performed whole exome sequencing on pairs of matched primary tumor and metastatic tissues from 65 mice. Analysis of this sequencing data identified recurrent metastasis-specific mutations in members of the Ras signaling pathway. One of the members was the SHC Adaptor Protein 1 (Shc1). Five PyMT animals carried different nucleotide substitutions within the same proline 561 codon that falls within the SH2 domain, suggesting an activating role in metastasis. Furthermore, changing this proline mutation to another amino acid could induce a critical change to the Shc1 protein structure and its function. To investigate the role of Shc1 in breast cancer metastasis, CRISPR was performed engineer Shc1 P561 mutations for in vitro and in vivo assays using a series of mouse mammary cancer cell lines and allograft mouse models. Preliminary evidence suggests the P561 mutations have a role in metastasis. Future experiments will address the consequences of the P561 mutation on Shc1 binding partner interactions and downstream signaling and its effects on breast cancer metastasis. Citation Format: Megan Majocha, Kent Hunter, Christina Ross. Shc1 as a potential metastasis driver gene of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2849.