학술논문
Initiation of human mammary cell tumorigenesis by mutant KRAS requires YAP inactivation
yes-associated protein 1
yes-associated protein 1
Document Type
Report
Author
Source
Oncogene. February 2020, Vol. 39 Issue 8, p1957, 12 p.
Subject
Language
English
ISSN
0950-9232
Abstract
Author(s): Sylvain Lefort [sup.1] , Susanna Tan [sup.1] , Sneha Balani [sup.1] , Bo Rafn [sup.2] , Davide Pellacani [sup.1] , Martin Hirst [sup.3] [sup.4] , Poul H. Sorensen [sup.2] [...]
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.sup.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.sup.G12D plus the constitutively active YAP.sup.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.sup.S127A. In addition, we show that YAP.sup.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.sup.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.
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.sup.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.sup.G12D plus the constitutively active YAP.sup.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.sup.S127A. In addition, we show that YAP.sup.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.sup.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.