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28-05-2022 | Breast Cancer | Preclinical study

COL8A1 facilitates the growth of triple-negative breast cancer via FAK/Src activation

Authors: Fumiaki Sato, Atsunobu Sagara, Kaede Tajima, Shotaro Miura, Kenjiro Inaba, Yusuke Ando, Teruaki Oku, Takashi Murakami, Yoshinori Kato, Tetsuro Yumoto

Published in: Breast Cancer Research and Treatment | Issue 2/2022

Abstract

Purpose

Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes, and treatment options are limited because of the lack of signature molecules and heterogeneous properties of cancer. COL8A1 expression is higher in breast cancer than in normal tissues and is strongly correlated with worse overall survival in patients with breast cancer. However, the biological function of COL8A1 on cancer progression is not fully understood. In this study, we investigated the biological function of COL8A1 on TNBC progression.

Methods

COL8A1-deficient cells were generated using the CRISPR-Cas9 system. The tumor growth and metastasis of TNBC cells were evaluated using three-dimensional culture (3D) methods and xenograft mouse models. The activation of focal adhesion kinase (FAK)/Src by COL8A1 in TNBC cells was evaluated by immunoblotting.

Results

COL8A1 expression was primarily distributed into TNBC cell lines. Further, relapse-free survival in TNBC patients with the MSL subtype was strongly associated with the COL8A1 expression. MDA-MB-231 and Hs578T cells, classified as the MSL subtype, strongly express COL8A1, and COL8A1 protein expression was induced by hypoxia in both cell lines. Loss of COL8A1 expression inhibited spheroid /tumor growth and metastasis in vitro and in vivo. Further, exogenous COL8A1 promoted TNBC growth via the FAK/Src activation. Finally, the spheroid growth of MDA-MB-231 and Hs578T cells was inhibited by defactinib, a FAK inhibitor, without cytotoxicity.

Conclusion

These results indicate that COL8A1-mediated FAK/Src activation produces a more aggressive phenotype in TNBC, and its target inhibition may be an efficacious treatment for TNBC.

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Title: COL8A1 facilitates the growth of triple-negative breast cancer via FAK/Src activation
Authors: Fumiaki Sato
Atsunobu Sagara
Kaede Tajima
Shotaro Miura
Kenjiro Inaba
Yusuke Ando
Teruaki Oku
Takashi Murakami
Yoshinori Kato
Tetsuro Yumoto
Publication date: 28-05-2022
Publisher: Springer US
Keywords: Breast Cancer
Breast Cancer
Published in: Breast Cancer Research and Treatment / Issue 2/2022
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-022-06635-y

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