Initiation of human mammary cell tumorigenesis by mutant KRAS requires YAP inactivation

• Published in: Oncogene 2020-02, Vol.39 (9), p.1957-1968
• Main Authors: Lefort, Sylvain, Tan, Susanna, Balani, Sneha, Rafn, Bo, Pellacani, Davide, Hirst, Martin, Sorensen, Poul H., Eaves, Connie J.
• Format: Article
• Language: English
• Subjects: 13/31; 13/51; 14/5; 42/100; 42/35; 42/44; 631/532/71; 631/67/1347; 631/67/70; 64; 82/80; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Amphiregulin; Amphiregulin - genetics; Amphiregulin - metabolism; Animals; Apoptosis; Breast - metabolism; Breast - pathology; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Biology; Cell Proliferation; Development and progression; Female; Gene mutations; Genetic aspects; Genetic transformation; Health aspects; Human Genetics; Humans; Immunodeficiency; Internal Medicine; Invasiveness; K-Ras protein; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Inbred NOD; Mice, SCID; Mutants; Mutation; Oncology; Proto-Oncogene Proteins p21(ras) - genetics; Signal Transduction; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Cells, Cultured; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yes-associated protein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-1111-0

High YAP activity is associated with poor prognosis human breast cancers, but its role during the initial stage of mammary cell transformation is unknown. To address this question, we designed experiments that exploit the ability of KRAS G12D -transduced subsets of freshly isolated normal human mammary cells to form invasive tumors rapidly and efficiently when transplanted into immunodeficient mice. Initial examination of the newly developing tumors thus generated revealed a consistent marked loss of nuclear YAP, independent of the initial primary human mammary cell type transduced. Conversely, co-transduction of the same subsets of primary human mammary cells with KRAS G12D plus the constitutively active YAP S127A prevented tumor formation. These findings contrast with the enhanced display of transformed properties obtained when the immortalized, but non-tumorigenic MCF10A cells are transduced just with YAP S127A . In addition, we show that YAP S127A -transduction of the human MDA-MB-231 breast cancer cell line (that carry a similar KRAS mutation) enhances their metastatic activity in vivo. We also discover that the KRAS G12D - induced early loss of YAP in primary human mammary cells is associated with their induced secretion of amphiregulin. Collectively, these findings suggest that YAP can differentially affect the acquisition of malignant properties by human mammary cells at different stages of their transformation.