Overcoming Bone Marrow Stroma-Mediated Chemoresistance in Metastatic Breast Cancer Cells
Annual rept. 7 Jul 2003-6 Jul 2004
UNIVERSITY OF MEDICINE AND DENTISTRY OFNEW JERSEY NEWARK
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Breast cancer cells that metastasize to the bone marrow early in the course of the disease can become dormant and are resistant to the chemotherapy given to eliminate them. We developed a model of dormancy in vitro where well-differentiated breast cancer cells incubated with basic fibroblast growth factor FGF-2 are growth-inhibited and upregulate integrins through which they receive survival signaling. Interaction between integrin alpha 5 beta 1 and fibronectin provides a survival advantage to dormant clones. Dormant cells have activated Akt and are resistant to docetaxel. Blocking Akt and P13 kinase, its upstream activator, using specific inhibitors reverses the survival advantage conferred by fibronectin but does not abrogate dormant clones completely. Blocking P13 kinase has the additional effect of disrupting the morphologic characteristics of dormant cells, suggesting a role for additional pathways besides Akt downstream of P13 kinase in dormant cell survival. A transcription inhibitor, flavopiridol, was very effective in diminishing survival of dormant clones. While it inhibited Akt phosphorylation, virally transduced replacement of Akt function did not reverse the inhibitory effects of flavopiridol. Flavopiridol reversed the upregulation of integrins and diminished adherence, particularly to fibronectin, supporting a role for this mechanism for its effects on dormant cells.
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