A cytoskeleton-based functional genetic screen identifies Bcl-xL as an enhancer of metastasis, but not primary tumor growth.
Many mouse models of breast cancer form large primary tumors that rarely metastasize. Models with aggressive metastasis express oncoproteins that simultaneously affect growth and apoptosis pathways. To define the role of apoptotic resistance and to model a challenge faced by tumor cells during metastatic dissemination, we focused on apoptosis induced by cell shape change. Inhibiting actin polymerization with Latrunculin-A causes cell rounding and death within hours in nontumorigenic human 10A-Ras mammary epithelial cells. In contrast, MDA-MB-231 metastatic breast tumor cells resist LA-induced death, and survive for days despite cell rounding. Infecting 10A-Ras cells with a MDA-MB-231 retroviral expression library, and selecting with Latrunculin-A repeatedly identified Bcl-xL as a suppressor of cytoskeleton-dependent death. Although Bcl-xL enhances the spread of metastatic breast tumor cell lines, the distinct effects of apoptotic resistance on tumor growth in the mammary gland and during metastasis have not been compared directly. We find that Bcl-xL overexpression in mouse mammary epithelial cells does not induce primary tumor formation or enhance MEK-induced tumorigenesis within the mammary gland environment. However, it strongly enhances metastatic potential. These results with Bcl-xL provide novel evidence that isolated apoptotic resistance can increase metastatic potential, but remain overlooked by assays based on breast tumor growth.
Martin
Stuart S
SS
Harvard Medical School, Department of Genetics, Howard Hughes Medical Institute, Boston, MA 02115, USA.
Ridgeway
Alan G
AG
Pinkas
Jan
J
Lu
Yu
Y
Reginato
Mauricio J
MJ
Koh
Eugene Y
EY
Michelman
Montserrat
M
Daley
George Q
GQ
Brugge
Joan S
JS
Leder
Philip
P
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003599:Cytoskeleton / Q000235:genetics*; D005821:Genetic Techniques; D005822:Genetic Vectors; D006801:Humans; D048369:MAP Kinase Kinase 1; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; D053778:Thiazolidines; D051020:bcl-X Protein; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C037067:latrunculin A