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 À/À ), 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 tumourinitiation 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 tumourinitiating ability. RNA-sequencing of human breast cancer cells, and mammary glands at hyperplastic stages and established tumours in PyMT and PyMT-miR-9 À/À 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.

miR-125 in Breast Cancer Etiopathogenesis: An Emerging Role as a Biomarker in Differential Diagnosis, Regenerative Medicine, and the Challenges of Personalized Medicine

“…Its role is well established in BC as well, where it acts as a tumor suppressor gene [ 211 ], regulates cell motility and invasion [ 212 ], endothelial differentiation [ 103 ], metastasis formation [ 213 , 214 ], cell migration [ 215 ], and apoptosis [ 216 ]. It has also been shown that STARD13 exerts its function in BC through its participation in many ceRNETs, such as the one involving a positive TGF-β/miR-9 regulatory loop mediated by the STARD13/YAP axis [ 217 ], the one involving hsa-miR-21-3p [ 218 ], or even the more complex network that involves five different miRs and that controls YAP/TAZ nuclear accumulation and transcriptional activity via modulation of Hippo and Rho-GTPase/F-actin signaling pathways [ 219 ]. A direct link between miR-125 and STARD13 expression has been described, too.…”

MiR‐9 promotes G‐MDSC recruitment and tumor proliferation by targeting SOCS3 in breast cancer

“…022974) and MMTV-PyMT miR-9 −/− mice were established by Shanghai Southern Model Biotechnology Co., Ltd. (Shanghai, China) using methods described in our previous study. 17 Animal feeding and animal experiment operations were strictly in accordance with the Animal Welfare and Ethics Committee (AWEC) of China Pharmaceutical University. To establish 4T1 tumor-bearing mice, murine breast cancer 4T1 cells (1 × 10 7 ) were inoculated into the ribs and lateral abdominal walls of BALB/c mice to induce tumor formation.…”

“…The processing method was described in detail in our previous article. 17 In brief, to prepare a single-cell suspension, mouse tissue was stripped and subjected to enzymolysis, filtration, and centrifugation. Then, the red blood cells were lysed and flushed immediately after treatment by flow cytometry sorting (FACS).…”

“…15,16 Our recent research demonstrated that miR-9 can augment the tumor-initiating potential of breast cancer cells through a transgenic mouse model. 17 Nevertheless, in the context of lung, 18 gastric, 19 and pancreatic 20 cancers, miR-9 might function as a tumor suppressor. Nonetheless, the intricate mechanisms through which miR-9 modulates the immune microenvironment in breast cancer remain incompletely elucidated.…”

Transcriptional factor BRD4 promotes the stemness of esophageal cancer by activating the nuclear PD‐L1/RelB axis

“…Cancer stem cells (CSCs) have emerged as a key focus in cancer research due to their involvement in tumor initiation, progression, and therapy resistance 3,4 . CSCs possess self‐renewal capabilities and exhibit high tumorigenic potential, contributing to tumor recurrence and metastasis 5 . Identifying the molecular mechanisms that regulate CSCs is of paramount importance for developing effective therapeutic strategies against EC.…”