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Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7683-7688. doi: 10.1073/pnas.1621486114. Epub 2017 Jul 3.

FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness.

Author information

1
Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin 150000, China.
2
Department of Breast Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
3
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
4
College of Basic Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, China.
5
Department of Pathology, Harbin Medical University, Harbin, Heilongjiang 150081, China.
6
Sydney Kimmel Cancer Center and Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21287.
7
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
8
Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.
9
Department of Pharmacology, School of Pharmacology, China Medical University, Shenyang 110122, China.
10
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 maria.new@mssm.edu tony.yuen@mssm.edu angel-s205@163.com.
11
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029; maria.new@mssm.edu tony.yuen@mssm.edu angel-s205@163.com.
12
Department of Breast Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; maria.new@mssm.edu tony.yuen@mssm.edu angel-s205@163.com.

Abstract

Fibrous sheath interacting protein 1 (FSIP1), a spermatogenesis-related testicular antigen, is expressed in abundance in breast cancers, particularly in those overexpressing human epidermal growth factor receptor 2 (HER2); however, little is known about its role in regulating the growth and metastasis of breast cancer cells. We and others have shown previously that FSIP1 expression in breast cancer correlates positively with HER2-positivity, recurrence, and metastases and negatively with survival. Here, using coimmunoprecipitation and microscale thermophoresis, we find that FSIP1 binds to the intracellular domain of HER2 directly. We further show that shRNA-induced FSIP1 knockdown in SKBR3 and MCF-7 breast cancer cells inhibits proliferation, stimulates apoptosis, attenuates epithelial-mesenchymal transition, and impairs migration and invasiveness. Consistent with reduced proliferation and enhanced apoptosis, xenotransplantation of SKBR3 cells stably transfected with sh-FSIP1 into nu/nu mice results in reduced tumor volumes compared with sh-NC transplants. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) mapping using sh-FSIP1 gene signature yielded associations with extracellular matrix protein pathways, and a reduction in SNAI2 protein expression was confirmed on Western blot analysis. Complementarily, interrogation of the Connectivity Map using the same gene signature yielded, as top hits, chemicals known to inhibit epithelial-mesenchymal transition, including rapamycin, 17-N-allylamino-17-demethoxygeldanamycin, and LY294002. These compounds phenocopy the effects of sh-FSIP1 on SKBR3 cell viability. Thus, FSIP1 suppression limits oncogenesis and invasiveness in breast cancer cells and, considering its absence in most other tissues, including normal breast, may become a potential target for breast cancer therapy.

KEYWORDS:

GO analysis; KEGG pathway analysis; breast cancer therapeutics; gene expression signature

PMID:
28674022
PMCID:
PMC5530656
DOI:
10.1073/pnas.1621486114
[Indexed for MEDLINE]
Free PMC Article

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