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Breast Cancer Research and Treatment

Erschienen in:

16.04.2021 | Preclinical study

NSDHL promotes triple-negative breast cancer metastasis through the TGFβ signaling pathway and cholesterol biosynthesis

verfasst von: Mengting Chen, Yang Zhao, Xueli Yang, Yuanyuan Zhao, Qiqi Liu, Yang Liu, Yifeng Hou, Hefen Sun, Wei Jin

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2021

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Abstract

Purpose

Metastasis is the main cause of breast cancer mortality. Recent studies have proved that lipid metabolic reprogramming plays critical roles in breast cancer carcinogenesis and metastasis. We aim to identify critical lipid metabolism genes in breast cancer metastasis.

Methods

We designed and cloned a CRISPR pooled library containing lipid metabolic gene guide RNAs and performed a genetic screen in vivo. Transwell assay and animal experiments were used to evaluate cell metastatic ability in vitro or in vivo, respectively. We performed immunohistochemistry with breast cancer tissue microarray to study the clinical significance of NSDHL.

Findings

We identified a cholesterol metabolic enzyme, NSDHL, as a potential metastatic driver in triple-negative breast cancer. NSDHL was highly expressed in breast cancer tissues and predicted a poor prognosis. NSDHL knockdown significantly suppressed cell proliferation and migration. Mechanistically, NSDHL activated the TGFβ signaling pathway by inhibiting the endosomal degradation of TGFβR2. In addition, blocking the upstream metabolism of NSDHL with ketoconazole rescued cancer metastasis and TGFβR2 degradation. However, the inactivation of NSDHL (Y151X) did not rescue the migration ability and the TGFβR2 protein expression.

Conclusion

Taken together, our findings established that NSDHL serves as a metastatic driver, and its function depends on its enzyme activity in cholesterol biosynthesis and is mediated by the NSDHL-TGFβR2 signal pathway. Our study indicated that NSDHL and steroid biosynthesis may serve as new drug targets for patients with advanced breast cancer.

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Titel: NSDHL promotes triple-negative breast cancer metastasis through the TGFβ signaling pathway and cholesterol biosynthesis
verfasst von: Mengting Chen
Yang Zhao
Xueli Yang
Yuanyuan Zhao
Qiqi Liu
Yang Liu
Yifeng Hou
Hefen Sun
Wei Jin
Publikationsdatum: 16.04.2021
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 2/2021
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-021-06213-8

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NSDHL promotes triple-negative breast cancer metastasis through the TGFβ signaling pathway and cholesterol biosynthesis