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. 2022 May;41(22):3064-3078.
doi: 10.1038/s41388-022-02320-y. Epub 2022 Apr 23.

MUC1 triggers lineage plasticity of Her2 positive mammary tumors

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

MUC1 triggers lineage plasticity of Her2 positive mammary tumors

Zhi Pang et al. Oncogene. 2022 May.

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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