A positive TGF-β/miR-9 regulatory loop promotes the expansion and activity of tumour-initiating cells in breast cancer.

Abstract

BACKGROUND AND PURPOSE:

MicroRNA-9 (miR-9) has previously been described as a dual-functional RNA during breast cancer progression and its roles need to be clarified thoroughly.

EXPERIMENTAL APPROACH:

A miR-9 knockout mode of mouse breast cancer, the MMTV-PyMT model (PyMT-miR-9-/- ), combined with different human breast cancer cell lines were used to evaluate the effects of miR-9 on breast cancer initiation, progression and metastasis. Lin-NECs (Neoplastic mammary epithelial cells) and pNECs (Pre-neoplastic mammary epithelial cells) were isolated and subjected to tumour-initiation assay. Whole-mount staining of mammary gland and histology was performed to determine mammary gland growth. Tumour-initiating analysis combining a series of in vitro experiments were carried out to evaluate miR-9 roles in tumour-initiating ability. RNA-sequencing of human breast cancer cells, and mammary glands at hyperplastic stages and established tumours in PyMT and PyMT-miR-9-/- mice, ChIP and luciferase report assays were conducted to reveal the underlying mechanisms.

KEY RESULTS:

MiR-9 is ectopically expressed in breast cancer and its level is negatively correlated with the prognosis, especially in basal-like breast cancer patients. Additionally, miR-9 is essential for breast cancer progression by promoting the expansion and activity of tumour-initiating cells (TICs) in preneoplastic glands, established tumours and xenograft modes. Mechanistically, the activity of TICs hinges on a positive TGF-β/miR-9 regulatory loop mediated by the STARD13/YAP axis.

CONCLUSIONS AND IMPLICATIONS:

These findings demonstrate that miR-9 is an oncogenic miRNA rather than a tumour-suppressor in breast cancer, calling for rectification of the model for this conserved and highly abundant miRNA.

• Authors: Yichen Liu, Ying Chen, Qiong Zhao, Tianyuan Xie, Chenxi Xiang, Qianqian Guo, Wenzhou Zhang, Yi Zhou, Yin Yuan, Yuxin Zhang, Tao Xi, Xiaoman Li, Lufeng Zheng
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 180 Issue 17 Pg. 2280-2297 (09 2023) ISSN: 1476-5381 [Electronic] England
• PMID: 37060166 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 British Pharmacological Society.

Chemical References

• Transforming Growth Factor beta
• MicroRNAs
• MIRN9 microRNA, mouse

Topics

• Humans
• Mice
• Animals
• Female
• Breast Neoplasms (metabolism)
• Transforming Growth Factor beta (metabolism)
• MicroRNAs (genetics, metabolism)
• Cell Transformation, Neoplastic (metabolism)
• Neoplastic Stem Cells
• Gene Expression Regulation, Neoplastic
• Cell Line, Tumor
• Cell Proliferation