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Short-hairpin RNA-guided single gene knockdown reverses triple-negative breast cancer

By Dong-Mei Chen, Zhu-Qing Shi, Li-Li Tan, Yan-Ping Chen, Chang-Qing Li, Qi Wang, He Li, Meng-Le Zhang, Jian-Ping Song, Qin Xu, Qing-Ping Zeng

Posted 15 Sep 2018
bioRxiv DOI: 10.1101/418764

Background: The origin of breast cancer remains poorly understood. Here, we testify a putative mechanism of "breast cancer origin from inducible nitric oxide synthase (iNOS) activation and oestrogen receptor alpha (ERα) inactivation", which are classified as the essential outcomes of chronic inflammatory responses. Methods: To reverse breast cancer status, iNOS was downregulated by short-hairpin RNA (shRNA)-guided NOS2 knockdown from human triple- negative breast cancer (TNBC) cells. To re-enact breast cancer origin, ERα was downregulated by shRNA-directed ESR1 knockdown in human mammary epithelial cells. Results: Upon NOS2 knockdown from HCC1937 cells, the specific TNBC transcription factor genes, RUNX1 and BCL11A, were downregulated, hypoxia was compromised, Warburg effects were attenuated, and tumourigenic proliferation was halted, accompanied by an increase in the tumour marker cyclin D1 (CD1) and a decrease in the tumour suppressor cyclin-dependent kinase inhibitor (CKI). In contrast, ESR1 knockdown from MCF-10A cells led to upregulated BCL11A and RUNX1 expression, augmented hypoxic responses, pronounced Warburg effects, and enhanced PI3K/Akt/mTOR signalling, together with low levels of CD1 and high levels of CKI induction. Conclusions: Breast cancer should originate from inflammatory signalling, during which iNOS activation and ERα inactivation elicit hypoxia, oxidation, mitochondrial dysfunction, and breast cancer-like hyperplasia, demonstrating that iNOS inhibitors and ERα activators represent promising candidate prodrugs enabling breast cancer prevention in the early stage.

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