Poster Sessions

CANCER-2

Yaqin Zhang

Y. Zhang, L. Risado Rivera, S.Y. Moon, B. Zhang

D4-GDI Regulation of Breast Cancer Invasive Phenotypes

D4-GDI is a Rho GDP dissociation inhibitor that is widely expressed in hematopoietic cells. In this study, we show that D4-GDI is selectively expressed in some breast cancer cell lines, but not in normal mammary epithelial cells. Knockdown of D4-GDI blocks cell motility and invasion of otherwise highly invasive MDA-MB-231 cells, and reverted their invasive to normal epithelial phenotypes. Importantly, D4-GDI depletion abolished tumor growth and lung metastasis of MDA-MB-231 cells in nude mice. Interestingly, D4-GDI-depelcted cells undergo spontaneous apoptosis at anchorage-independent conditions – anoikis that has been implicated in hindering metastasis. We also found that D4-GDI selectively binds Rac1 and Rac3 in breast cancer cells, but not other Rho GTPases tested (Cdc42, RhoA, RhoC, or TC10). Loss of D4-GDI resulted in constitutive Rac1 activation, its translocation from cytosol to cellular membranes, and sustained activation of p38/JNK kinase pathways. Blockade of these pathways reversed D4-GDI-knockdown induced anoikis. Furthermore, tissue array (n=208) analysis revealed a biphasic pattern of D4-GDI expression i.e. it increases from normal to benign and peaks in early stages of tumors, thereafter decreases in malignant and metastatic tumors. The results show that D4-GDI plays an integral role in breast tumorigenesis. D4-GDI could be an prognostic marker of invasive breast cancers.