Breast cancer has a high propensity to metastasize to bone. While the genetic and
epigenetic changes associated with metastatic breast cancer progression are being
identified, the changes that drive metastatic progression are poorly understood.
Proteases, and in particular matrix metalloproteinases (MMPs), have been shown to play
a pivotal role in certain aspects of tumor metastasis by modifying the affected
microenvironment. Bone matrix-depositing mouse MC3T3 osteoblasts were co-cultured
with metastatic human MDA-MB-23 1 (MDA23 1) cells or the bone-homing MDA-MB
231-1 833/TR (1 833/TR) variant in an effort to identify novel, osteoclast-independent,
changes to the tumor/bone microenvironment. Co-culture-induced changes in the
complete “protease and inhibitor” expression profile in the osteoblasts and the tumor
cells were then determined using targeted murine and human specific microarray chips
(CLIP-CHIP TM ). This analysis revealed an increase in the RNA expression of
collagenase-3 (MMP 13) in the co-cultured osteoblasts that was confirmed by qPCR.
Further, Western blotting indicated increased MIvIP13 protein secretion into the bone
matrixltumor microenvironment by the co-cultured MC3T3 cells.
The elevation in osteoblast-produced MMP13 was observed when the co-
cultured tumor cells were in direct contact or separated by filters. Additionally, the
elevation was also induced by conditioned medium derived from separate MDA23 1 or
1 833/TR cultures, which indicates that a soluble factor produced by the tumor cells is
capable of inducing MMP 13. One soluble factor that appears to be produced by 1 833iTR
cultures is oncostatin M. Oncostatin M is an interleukin-6 family cytokine that is known
to upregulate MMP13 synthesis and secretion during chondrogenesis. Genome-wide
Affymetrix® analysis revealed, and qPCR analysis confirmed, that oncostatin M
receptor-specific subunit RNA was also significantly upregulated in co-cultured
osteoblasts. Therefore, breast tumor cells may be capable of initiating protein
degradative changes in the bone microenvironment that are independent of the much
studied osteolytic degradation initiated by osteoclast activation.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:BVAU./4179 |
| Date | 11 1900 |
| Creators | Mancini, Stephanie Sarah Jane |
| Publisher | University of British Columbia |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | 4145263 bytes, application/pdf |
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