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MUC1 triggers lineage plasticity of Her2 positive mammary tumors

Oncogene volume 41, pages 3064–3078 (2022)Cite this article

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Abstract

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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Fig. 1: Patients co-overexpressing MUC1 and HER2 display a worse clinical outcome.
Fig. 2: MUC1-CD and Her2 accelerate mammary tumorigenesis and cause lineage plasticity in a transgenic mouse model.
Fig. 3: MUC1-CD triggers metabolic gene reprogramming.
Fig. 4: Depletion of MUC1 rescues TCA gene expression and reverses breast carcinogenesis.
Fig. 5: Deficiency of TCA genes is correlated with short survival time in HER2+ breast cancer patients.
Fig. 6: Efnb1 expression is regulated by MUC1.
Fig. 7: MUC1-CD actives the Her2 signaling pathway by prompting dimerization of EGFR and Her2.
Fig. 8: Schematic overview of the work model.

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Data availability

The microarray data were deposited in the Gene Expression Omnibus with the accession code GSE198239. All other data generated and backing the results and conclusions of this study are available from the corresponding author on reasonable request.

Code availability

The code used will be made available upon request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant numbers 81874197 and 82073111), Science and Technology Commission of Shanghai Municipality (grant number 21S11901600) to Huang L. The authors appreciate Dr. Shuhai Lin for constructive suggestions.

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Author notes

  1. These authors contributed equally: Zhi Pang, Xinran Dong, Huayun Deng.

Authors and Affiliations

  1. Department of Histoembryology, Genetics and Developmental Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

    Zhi Pang, Huayun Deng, Chengzhi Wang, Xiaodong Liao, Chunhua Liao, Jinke Cheng, Guoqiang Chen & Lei Huang

  2. Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, People’s Republic of China

    Zhi Pang

  3. Center for Molecular Medicine, Children’s Hospital of Fudan University, Shanghai, People’s Republic of China

    Xinran Dong & Weidong Tian

  4. Department of Pharmacy, Huangpu branch of the Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

    Yahui Liao

  5. State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Department of Computational Biology, School of Life Sciences, Fudan University, Shanghai, People’s Republic of China

    Weidong Tian

  6. Department of Breast Surgery, Huangpu branch of the Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

    Haiying Yi

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Contributions

LH designed research; JC and GC contributed constructive suggestions; ZP, HD, CW, and XL performed research; ZP, XD, and CL contributed tumor tissues sequencing analysis and database analysis; HY provided patients tumor tissue samples; ZP, YL, and LH wrote the paper.

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Correspondence to Haiying Yi or Lei Huang.

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Pang, Z., Dong, X., Deng, H. et al. MUC1 triggers lineage plasticity of Her2 positive mammary tumors. Oncogene 41, 3064–3078 (2022). https://doi.org/10.1038/s41388-022-02320-y

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