SH3BGRL2 exerts a dual function in breast cancer growth and metastasis and is regulated by TGF-β1

Dou-Dou Li; Ling Deng; Shu-Yuan Hu; Fang-Lin Zhang; Da-Qiang Li

SH3BGRL2 exerts a dual function in breast cancer growth and metastasis and is regulated by TGF-β1

Am J Cancer Res. 2020 Apr 1;10(4):1238-1254. eCollection 2020.

Authors

Dou-Dou Li^{1

2

3}, Ling Deng¹, Shu-Yuan Hu¹, Fang-Lin Zhang^{1

2

3}, Da-Qiang Li^{1

2

3

4}

Affiliations

¹ Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University Shanghai 200032, China.
² Cancer Institute, Shanghai Medical College, Fudan University Shanghai 200032, China.
³ Department of Oncology, Shanghai Medical College, Fudan University Shanghai 200032, China.
⁴ Shanghai Key Laboratory of Breast Cancer, Shanghai Medical College, Fudan University Shanghai 200032, China.

PMID: 32368399
PMCID: PMC7191107

Abstract

SH3 domain-binding glutamic acid-rich-like protein 2 (SH3BGRL2) is a poorly defined member of the SH3BGR gene family with potential roles in cell differentiation and tissue development. Here, we report for the first time that SH3BGRL2 exerts a dual function in breast tumor growth and metastasis. SH3BGRL2 was downregulated in a subset of primary breast tumors, and suppressed breast cancer cell proliferation and colony formation in vitro and xenograft tumor growth in vivo. Strikingly, SH3BGRL2 enhanced breast cancer cell migratory, invasive, and lung metastatic capacity. Mechanistic investigations revealed that SH3BGRL2 interacted with and transcriptionally repressed spectrin alpha, non-erythrocytic 1 (SPTAN1) and spectrin beta, non-erythrocytic 1 (SPTBN1), two important cytoskeletal proteins. Functional rescue assays further demonstrated that depletion of SH3BGRL2 reduced breast cancer cell invasive potential, which was partially rescued by knockdown of SPTAN1 and SPTBN1 using specific small interfering RNA. Moreover, transforming growth factor-β1 (TGF-β1) transcriptionally activated SH3BGRL2 expression in breast cancer cells through the canonical TGF-β receptor-Smad pathway. Collectively, these results establish a dual function of SH3BGRL2 in breast cancer growth and metastasis and uncover SH3BGRL2 as a downstream target of the TGF-β1 signaling pathway in breast cancer cells.

Keywords: Breast cancer; SH3BGRL2; SPTAN1; SPTBN1; TGF-β signaling.