Downregulation of miR-223 Expression Is an Early Event during Mammary Transformation and Confers Resistance to CDK4/6 Inhibitors in Luminal Breast Cancer.

Abstract

miR-223 is an anti-inflammatory miRNA that in cancer acts either as an oncosuppressor or oncopromoter, in a context-dependent manner. In breast cancer, we demonstrated that it dampens the activation of the EGF pathway. However, little is known on the role of miR-223 during breast cancer onset and progression. miR-223 expression was decreased in breast cancer of luminal and HER2 subtypes and inversely correlated with patients' prognosis. In normal luminal mammary epithelial cells, miR-223 acted cell autonomously in the control of their growth and morphology in three-dimensional context. In the MMTV-Δ16HER2 transgenic mouse model, oncogene transformation resulted in a timely abrogation of miR-223 expression, likely due to activation of E2F1, a known repressor of miR-223 transcription. Accordingly, treatment with CDK4/6 inhibitors, which eventually results in restraining E2F1 activity, restored miR-223 expression and miR-223 ablation induced luminal breast cancer resistance to CDK4/6 inhibition, both in vitro and in vivo. Notably, miR-223 expression was lost in microdissected ductal carcinoma in situ (DCIS) from patients with luminal and HER2-positive breast cancer. Altogether, these results identify downmodulation of miR-223 as an early step in luminal breast cancer onset and suggest that it could be used to identify aggressive DCIS and predict the response to targeted therapy. SIGNIFICANCE: miR-223 may represent a predictive biomarker of response to CDK4/6 inhibitors and its loss could identify DCIS lesions that are likely to progress into invasive breast cancer.

• Authors: Francesca Citron, Ilenia Segatto, Gian Luca Rampioni Vinciguerra, Lorena Musco, Francesca Russo, Giorgia Mungo, Sara D'Andrea, Maria Chiara Mattevi, Tiziana Perin, Monica Schiappacassi, Samuele Massarut, Cristina Marchini, Augusto Amici, Andrea Vecchione, Gustavo Baldassarre, Barbara Belletti
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 5 Pg. 1064-1077 (03 01 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 31862778 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• E2F1 Transcription Factor
• E2F1 protein, human
• MIRN223 microRNA, human
• MIRN223 microRNA, mouse
• MicroRNAs
• Piperazines
• Pyridines
• ERBB2 protein, human
• Receptor, ErbB-2
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• palbociclib

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Breast (cytology, pathology)
• Breast Neoplasms (drug therapy, genetics, mortality, pathology)
• Carcinoma, Intraductal, Noninfiltrating (drug therapy, genetics, mortality, pathology)
• Cell Culture Techniques
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• Disease Models, Animal
• Disease Progression
• Down-Regulation
• Drug Resistance, Neoplasm (genetics)
• E2F1 Transcription Factor (metabolism)
• Epithelial Cells
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mammary Glands, Animal (cytology, pathology)
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Neoplasm Invasiveness (genetics)
• Piperazines (pharmacology, therapeutic use)
• Prognosis
• Pyridines (pharmacology, therapeutic use)
• Receptor, ErbB-2 (genetics, metabolism)