Regulation of breast cancer response to chemotherapy by fibulin-1.
Doxorubicin treatment was found to augment the expression of the extracellular matrix (ECM) protein fibulin-1 in cultured human breast cancer cell lines and in MDA-MB-361 tumors grown in athymic mice. Doxorubicin was also found to augment tumor expression of the fibulin-1-binding proteins fibronectin and laminin-1. Growth of breast cancer cell lines on Matrigel, an ECM extract containing fibulin-1 and laminin-1, resulted in lower levels of doxorubicin-induced apoptosis as compared with controls. Moreover, tumors formed by injection of athymic mice with MDA-MB-361 cells mixed with Matrigel were significantly more doxorubicin resistant and displayed lower levels of apoptosis compared with those that formed in the absence of Matrigel. Monoclonal antibodies against fibulin-1 reversed Matrigel-dependent doxorubicin resistance. Furthermore, small interfering RNA-mediated suppression of fibulin-1 expression in breast cancer cells resulted in a 10-fold increase in doxorubicin sensitivity as compared with control cells. Together, these findings point to a role for fibulin-1 in breast cancer chemoresistance.
Pupa
Serenella M
SM
Molecular Biology Unit, Department of Experimental Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Giuffré
Sarah
S
Castiglioni
Fabio
F
Bertola
Lorenzo
L
Cantú
Marco
M
Bongarzone
Italia
I
Baldassari
Paola
P
Mortarini
Roberta
R
Argraves
W Scott
WS
Anichini
Andrea
A
Menard
Sylvie
S
Tagliabue
Elda
E
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
D000903:Antibiotics, Antineoplastic; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D034741:RNA, Small Interfering; C060820:fibulin; D004317:Doxorubicin