Pupa Serenella M, Giuffré Sarah, Castiglioni Fabio, Bertola Lorenzo, Cantú Marco, Bongarzone Italia, Baldassari Paola, Mortarini Roberta, Argraves W Scott, Anichini Andrea, Menard Sylvie, Tagliabue Elda
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.
Cancer Res. 2007 May 1;67(9):4271-7. doi: 10.1158/0008-5472.CAN-06-4162.
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.
研究发现，阿霉素治疗可增强培养的人乳腺癌细胞系以及无胸腺小鼠体内生长的MDA - MB - 361肿瘤中细胞外基质（ECM）蛋白纤维连接蛋白-1的表达。还发现阿霉素可增强肿瘤中与纤维连接蛋白-1结合的蛋白纤连蛋白和层粘连蛋白-1的表达。与对照组相比，乳腺癌细胞系在含有纤维连接蛋白-1和层粘连蛋白-1的ECM提取物基质胶上生长时，阿霉素诱导的细胞凋亡水平较低。此外，将MDA - MB - 361细胞与基质胶混合注射到无胸腺小鼠体内形成的肿瘤，与未添加基质胶形成的肿瘤相比，对阿霉素的耐药性明显更强，且细胞凋亡水平更低。抗纤维连接蛋白-1单克隆抗体可逆转基质胶依赖性阿霉素耐药性。此外，与对照细胞相比，小干扰RNA介导的乳腺癌细胞中纤维连接蛋白-1表达的抑制使阿霉素敏感性提高了10倍。这些研究结果共同表明纤维连接蛋白-1在乳腺癌化疗耐药中起作用。
