RhoC impacts the metastatic potential and abundance of breast cancer stem cells.
Cancer stem cells (CSCs) have been shown to promote tumorigenesis of many tumor types, including breast, although their relevance to cancer metastasis remains unclear. While subpopulations of CSCs required for metastasis have been identified, to date there are no known molecular regulators of breast CSC (BCSC) metastasis. Here we identify RhoC GTPase as an important regulator of BCSC metastasis, and present evidence suggesting that RhoC also modulates the frequency of BCSCs within a population. Using an orthotopic xenograft model of spontaneous metastasis we discover that RhoC is both necessary and sufficient to promote SUM149 and MCF-10A BCSC metastasis--often independent from primary tumor formation--and can even induce metastasis of non-BCSCs within these cell lines. The relationship between RhoC and BCSCs persists in breast cancer patients, as expression of RhoC and the BCSC marker ALDH1 are highly correlated in clinical specimens. These results suggest new avenues to combating the deadliest cells driving the most lethal stage of breast cancer progression.
Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Devin T
DT
Rosenthal
Jie
J
Zhang
Liwei
L
Bao
Lian
L
Zhu
Zhifen
Z
Wu
Kathy
K
Toy
Celina G
CG
Kleer
Sofia D
SD
Merajver
D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D050697:Retinal Dehydrogenase / Q000378:metabolism; D014183:Transplantation, Heterologous; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein