Journal
ONCOGENE
Volume 41, Issue 22, Pages 3064-3078Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-022-02320-y
Keywords
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Funding
- National Natural Science Foundation of China [81874197, 82073111]
- Science and Technology Commission of Shanghai Municipality [21S11901600]
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Aberrant overexpression of MUC1 and HER2 is associated with breast cancer, and their concomitant expression leads to worse clinical outcome. In a mouse model, coexpression of Her2 and MUC1-CD promotes mammary tumor development and induces changes in tumor lineage plasticity and downregulation of tricarboxylic acid cycle genes. Furthermore, MUC1 enhances the Her2 signaling pathway by inducing Her2/Egfr dimerization.
Aberrant overexpression of mucin 1 (MUC1) and human epidermal growth factor receptor 2 (HER2) are often observed in breast cancer. However, the role of concomitant MUC1/HER2 in the development of breast cancer has not been fully illustrated. Following analysis of public microarray datasets that revealed a correlation between double MUC1 and HER2 positivity and a worse clinical outcome, we generated a mouse model overexpressing both Her2 and MUC1 cytoplasmic domain (MUC1-CD) to investigate their interaction in mammary carcinogenesis. Coexpression of Her2 and MUC1-CD conferred a growth advantage and promoted the development of spontaneous mammary tumors. Genomic analysis revealed that enforced expression of MUC1-CD and Her2 induces mammary tumor lineage plasticity, which is supported by gene reprogramming and mammary stem cell enrichment. Through gain- and loss-of-function strategies, we show that coexpression of Her2 and MUC1-CD is associated with downregulation of tricarboxylic acid (TCA) cycle genes in tumors. Importantly, the reduction in TCA cycle genes induced by MUC1-CD was found to be significantly connected to poor prognosis in HER2(+) breast cancer patients. In addition, MUC1 augments the Her2 signaling pathway by inducing Her2/Egfr dimerization. These findings collectively demonstrate the vital role of MUC1-CD/Her2 collaboration in shaping the mammary tumor landscape and highlight the prognostic and therapeutic implications of MUC1 in patients with HER2(+) breast cancer.
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