SIVA mutation, a candidate metastasis gene identified from clonally related bilateral breast cancers, promotes breast cancer cell aggressiveness in vitro and in vivo

ABSTRACT: Our purpose is to identify candidate genes involved in the early steps of breast cancer metastasis and examine their pro-invasive functions both in vitro and in vivo. A percentage of bilateral breast cancers were clonally related based on copy number variation profiling. Whole exome sequencing and comparative sequence analysis revealed that a limited number of somatic mutations were acquired in this “breast to breast” metastasis. These mutations might promote breast cancer distant spread. The pro-invasive functions of a candidate metastasis gene were assessed in vitro by its abilities to promote proliferation, migration and invasion and in vivo as tumor xenografts in immunocompromised mice or a syngeneic orthotopic mouse breast cancer model. RNAseq analysis was performed to probe the transcription programs modulated by this candidate metastasis gene. SIVA1-D160N was one somatic mutation acquired in the breast to breast metastasis. Over-expression of SIVA1-D160N promoted migration and invasion of human MB-MDA-231 breast cancer cells in vitro, consistent with a dominant negative interfering function. When introduced via tail vein injection, 231 cells over-expressing SIVA1-D160N displayed enhanced distant spread on IVIS imaging. Over-expression of SIVA1-D160N promoted anchorage independent growth of mouse 4T1 breast cancer cells in vitro. When introduced orthotopically via mammary fat pad injection in syngeneic Balb/c mice, over-expression of SIVA1-D160N in 4T1 cells increased mammary gland tumor growth as well as liver metastasis. We conclude clonally related bilateral breast cancers represent a novel system to investigate metastasis and revealed a role of SIVA1-D160N in breast cancer metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242210 | GEO | 2024/05/15

REPOSITORIES: GEO