Open AccessDual inhibition of Wnt and Yes‐associated protein signaling retards the growth of triple‐negative breast cancer in both mesenchymal and epithelial states
Author(s) -
Sulaiman Andrew,
McGarry Sarah,
Li Li,
Jia Deyong,
Ooi Sarah,
Addison Christina,
Dimitroulakos Jim,
Arnaout Angel,
Nessim Carolyn,
Yao Zemin,
Ji Guang,
Song Haiyan,
Gadde Suresh,
Li Xuguang,
Wang Lisheng
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12167
Subject(s) - wnt signaling pathway , cancer research , mesenchymal stem cell , carcinogenesis , triple negative breast cancer , epithelial–mesenchymal transition , breast cancer , cancer stem cell , biology , cancer , signal transduction , stem cell , microbiology and biotechnology , metastasis , genetics
Triple‐negative breast cancer ( TNBC ), the most refractory subtype of breast cancer to current treatments, accounts disproportionately for the majority of breast cancer‐related deaths. This is largely due to cancer plasticity and the development of cancer stem cells ( CSC s). Recently, distinct yet interconvertible mesenchymal‐like and epithelial‐like states have been revealed in breast CSC s. Thus, strategies capable of simultaneously inhibiting bulk and CSC populations in both mesenchymal and epithelial states have yet to be developed. Wnt/β‐catenin and Hippo/ YAP pathways are crucial in tumorigenesis, but importantly also possess tumor suppressor functions in certain contexts. One possibility is that TNBC cells in epithelial or mesenchymal state may differently affect Wnt/β‐catenin and Hippo/ YAP signaling and CSC phenotypes. In this report, we found that YAP signaling and CD 44 high / CD 24 −/low CSC s were upregulated while Wnt/β‐catenin signaling and ALDH + CSC s were downregulated in mesenchymal‐like TNBC cells, and vice versa in their epithelial‐like counterparts. Dual knockdown of YAP and Wnt/β‐catenin, but neither alone, was required for effective suppression of both CD 44 high / CD 24 −/low and ALDH + CSC populations in mesenchymal and epithelial TNBC cells. These observations were confirmed with cultured tumor fragments prepared from patients with TNBC after treatment with Wnt inhibitor ICG ‐001 and YAP inhibitor simvastatin. In addition, a clinical database showed that decreased gene expression of Wnt and YAP was positively correlated with decreased ALDH and CD 44 expression in patients’ samples while increased patient survival. Furthermore, tumor growth of TNBC cells in either epithelial or mesenchymal state was retarded, and both CD 44 high / CD 24 −/low and ALDH + CSC subpopulations were diminished in a human xenograft model after dual administration of ICG ‐001 and simvastatin. Tumorigenicity was also hampered after secondary transplantation. These data suggest a new therapeutic strategy for TNBC via dual Wnt and YAP inhibition.