TY - JOUR
T1 - St8SIA1 regulates tumor growth and metastasis in TNBC by activating the FAK–AkT–mTOR signaling pathway
AU - Nguyen, Khoa
AU - Yan, Yuanqing
AU - Yuan, Bin
AU - Dasgupta, Abhishek
AU - Sun, Jeffrey
AU - Mu, Hong
AU - Do, Kim Anh
AU - Ueno, Naoto T.
AU - Andreeff, Michael
AU - Lokesh Battula, V.
N1 - Funding Information:
This work is supported by grants from the Breast Cancer Research Foundation (BCRF), the MD Anderson Cancer Center Support Grant (CA016672), the Paul and Mary Haas Chair in Genetics (to M. Andreeff), and the Berdon Lawrence Research Award from Bone Disease Program of Texas (to V.L. Battula).
Publisher Copyright:
©2018 American Association for Cancer Research.
PY - 2018/12
Y1 - 2018/12
N2 - Breast cancer stem-like cells (BCSC) are implicated in cancer recurrence and metastasis of triple-negative breast cancer (TNBC). We have recently discovered that ganglioside GD2 expression defines BCSCs and that ST8SIA1 regulates GD2 expression and BCSC function. In this report, we show that ST8SIA1 is highly expressed in primary TNBC; its expression is positively correlated with the expression of several BCSC-associated genes such as BCL11A, FOXC1, CXCR4, PDGFRb, SOX2, and mutations in p53. CRISPR knockout of ST8SIA1 completely inhibited BCSC functions, including in vitro tumorigenesis and mammosphere formation. Mechanistic studies discovered activation of the FAK–AKT–mTOR signaling pathway in GD2þ BCSCs, and its tight regulation by ST8SIA1. Finally, knockout of ST8SIA1 completely blocked in vivo tumor growth and metastasis by TNBC cells. In summary, these data demonstrate the mechanism by which ST8SIA1 regulates tumor growth and metastasis in TNBC and identifies it as a novel therapeutic target.
AB - Breast cancer stem-like cells (BCSC) are implicated in cancer recurrence and metastasis of triple-negative breast cancer (TNBC). We have recently discovered that ganglioside GD2 expression defines BCSCs and that ST8SIA1 regulates GD2 expression and BCSC function. In this report, we show that ST8SIA1 is highly expressed in primary TNBC; its expression is positively correlated with the expression of several BCSC-associated genes such as BCL11A, FOXC1, CXCR4, PDGFRb, SOX2, and mutations in p53. CRISPR knockout of ST8SIA1 completely inhibited BCSC functions, including in vitro tumorigenesis and mammosphere formation. Mechanistic studies discovered activation of the FAK–AKT–mTOR signaling pathway in GD2þ BCSCs, and its tight regulation by ST8SIA1. Finally, knockout of ST8SIA1 completely blocked in vivo tumor growth and metastasis by TNBC cells. In summary, these data demonstrate the mechanism by which ST8SIA1 regulates tumor growth and metastasis in TNBC and identifies it as a novel therapeutic target.
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U2 - 10.1158/1535-7163.MCT-18-0399
DO - 10.1158/1535-7163.MCT-18-0399
M3 - Article
C2 - 30237308
AN - SCOPUS:85057594388
SN - 1535-7163
VL - 17
SP - 2689
EP - 2701
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 12
ER -