Full Text | PDF

Theranostics 2020; 10(10):4644-4658. doi:10.7150/thno.43150 This issue Cite

Research Paper

Nuclear translocation of PLSCR1 activates STAT1 signaling in basal-like breast cancer

Panpan Huang^1,2, Ruocen Liao^1,2, Xingyu Chen^1,2, Xuebiao Wu³, Xiaoli Li^1,2, Yifan Wang^1,2,4, Qianhua Cao^1,2, Chenfang Dong^1,2,3✉

1. Department of Pathology and Pathophysiology, and Department of Surgical Oncology (breast center) of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
2. Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
3. Department of Pathophysiology, Zunyi Medical University, Zunyi 563000, China
4. Cancer Institute of Integrative Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China.

✉ Corresponding author: Chenfang Dong, MD, PhD, E-mail: chenfangdongedu.cn; Phone: +86 571 88208990; Fax: +86 571 88208990

Abstract

Rationale: Basal-like breast cancer (BLBC) is associated with high grade, distant metastasis, and poor prognosis; however, the mechanism underlying aggressiveness of BLBC is still unclear. Emerging evidence has suggested that phospholipid scramblase 1 (PLSCR1) is involved in tumor progression. Here, we aimed to study the possible involvement and molecular mechanisms of PLSCR1 contributing to the aggressive behavior of BLBC.

Methods: The potential functions of PLSCR1 in breast cancer cells were assessed by Western blotting, colony formation, migration and invasion, Cell Counting Kit-8 assay, mammosphere formation and flow cytometry. The relationship between nuclear translocation of PLSCR1 and transactivation of STAT1 was examined by immunostaining, co-IP, ChIP, and quantitative reverse transcription PCR. The effect of PLSCR1 expression on BLBC cells was determined by in vitro and in vivo tumorigenesis and a lung metastasis mouse model.

Results: Compared to other subtypes, PLSCR1 was considerably increased in BLBC. Phosphorylation of PLSCR1 at Tyr 69/74 contributed to the nuclear translocation of this protein. PLSCR1 was enriched in the promoter region of STAT1 and enhanced STAT3 binding to the STAT1 promoter, resulting in transactivation of STAT1; STAT1 then enhanced cancer stem cell (CSC)-like properties that promoted BLBC progression. The knockdown of PLSCR1 led to significant inhibitory effects on proliferation, migration, invasion, tumor growth and lung metastasis of BLBC cells. Clinically, high PLSCR1 expression was strongly correlated with large tumor size, high grade, metastasis, chemotherapy resistance, and poor survival, indicating poor prognosis in breast cancer patients.

Conclusions: Our data show that overexpression and nuclear translocation of PLSCR1 provide tumorigenic and metastatic advantages by activating STAT1 signaling in BLBC. This study not only reveals a critical mechanism of how PLSCR1 contributes to BLBC progression, but also suggests potential prognostic indicators and therapeutic targets for this challenging disease.

Keywords: PLSCR1, basal-like breast cancer, STAT3, STAT1 signaling, cancer stem cells

Citation styles

©2024 Ivyspring International Publisher. Terms of use