2. Academic Validation
  3. MUC1 triggers lineage plasticity of Her2 positive mammary tumors

MUC1 triggers lineage plasticity of Her2 positive mammary tumors

  • Oncogene. 2022 May;41(22):3064-3078. doi: 10.1038/s41388-022-02320-y.
Zhi Pang  # 1 2,  Xinran Dong  # 3,  Huayun Deng  # 1,  Chengzhi Wang 1,  Xiaodong Liao 1,  Chunhua Liao 1,  Yahui Liao 4,  Weidong Tian 3 5,  Jinke Cheng 1,  Guoqiang Chen 1,  Haiying Yi 6,  Lei Huang 7
Affiliations

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.
  • 2 Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, People's Republic of China.
  • 3 Center for Molecular Medicine, Children's Hospital of Fudan University, Shanghai, People's Republic of China.
  • 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.
  • 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.
  • 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. yihaiying@163.com.
  • 7 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. leihuang@shsmu.edu.cn.
  • # Contributed equally.
PMID: 35461328 DOI: 10.1038/s41388-022-02320-y
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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