Overcoming Bone Marrow Stroma-Mediated Chemoresistance in Metastatic Breast Cancer Cells
Abstract
Well-differentiated breast cancer cells metastasize to the bone marrow where they can remain dormant for years and are resistant to chemotherapy. We have developed an in vitro model where well-differentiated breast cancer cell lines treated with FGF-2, a growth factor abundant in the marrow microenvironment, stop proliferating, partially re-differentiate by re-expressing novel integrins such as alpha 5 beta 1 though which they ligate bone marrow fibronectin and receive survival signaling. This signaling includes sustained activation of the PI3 kinase/Akt pathway. Here, we demonstrate that all trans- retinoic acid (ATRA) inhibits Akt phosphorylation and inhibits survival of dormant clones in a dose-dependent manner at concentrations achievable in vivo. Cells treated with ATRA lose the characteristic morphology of these dormant cellsand appear stellate and shrunken. We investigated the effects of the small GTPase Rho, with reported roles in cell spreading. Blocking Rho and its downstream kinase ROCK inhibited survival of dormant clones in a dose-dependent manner. Combined blockade of PI3 kinase and Rho or ROCK achieved a synergistic inhibition of dormant clone survival, resulting in their nearly total abrogation. These data suggest that combined blockade of these signaling pathways may merit study of their effects on eliminating dormant breast cancer cells in the marrow.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2005
- Accession Number
- ADA442681
Entities
People
- Robert Wieder
Organizations
- New Jersey Medical School