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

• Published in: PloS one Vol. 19; no. 5; p. e0302856
• Main Authors: Vermehren-Schmaedick, Anke, Peto, Myron, Wagoner, Wendy, Chiotti, Kami E, Ramsey, Elizabeth, Wang, Xiaoyan, Rakshe, Shauna, Minnier, Jessica, Sears, Rosalie, Spellman, Paul, Luoh, Shiuh-Wen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.05.2024; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biology and Life Sciences; Biomarkers; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cancer therapies; Cell Line, Tumor; Cell Movement - genetics; Colorectal cancer; Copy number; Development and progression; Diagnosis; DNA Copy Number Variations; Enzymes; Ethylenediaminetetraacetic acid; Female; Gene mutations; Genetic aspects; Health aspects; Humans; Injection; International economic relations; Mammary gland; Mammary glands; Medical prognosis; Medicine and Health Sciences; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mutation; Neomycin; Neoplasm Invasiveness; Neoplasm Metastasis; Oncology, Experimental; Ovarian cancer; Ovaries; Overexpression; Patients; Phenotypes; Physiological aspects; Proteins; Scientific equipment and supplies industry; Sequences; Therapeutic targets; Tumors; Whole genome sequencing; United States; Oregon; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0302856

Metastasis is the most dreaded outcome after a breast cancer diagnosis, and little is known regarding what triggers or promotes breast cancer to spread distally, or how to prevent or eradicate metastasis effectively. Bilateral breast cancers are an uncommon form of breast cancers. In our study, 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 that might promote breast cancer distant spread. One somatic mutation acquired was SIVA-D160N that displayed pro-metastatic phenotypes in vivo and in vitro. Over-expression of SIVA-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 SIVA-D160N displayed enhanced distant spread on IVIS imaging. Over-expression of SIVA-D160N promoted invasion and 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 SIVA-D160N in 4T1 cells increased orthotopically implanted mammary gland tumor growth as well as liver metastasis. Clonally related bilateral breast cancers represented a novel system to investigate metastasis and revealed a role of SIVA-D160N in breast cancer metastasis. Further characterization and understanding of SIVA function, and that of its interacting proteins, may elucidate mechanisms of breast cancer metastasis, providing clinically useful biomarkers and therapeutic targets.