Bone metastasis in breast cancer causes profound morbidity. This complication is driven by tumor-bone microenvironment interactions where the details remain sketchy. Nevertheless, compelling evidence suggests the osteoclast (OC) is the cell ultimately responsible for bone metastasis. A symbiotic relationship is established between tumor and OC where the tumor cell first secretes osteoclastogenic factors which stimulate OC-mediated osteolysis releasing mitogenic factors which favor additional tumor growth. We suggest that breaking the interdependency between tumor and OC may provide an effective strategy to halt bone metastases. Therefore, understanding how breast cancer cells create such a highly osteoclastogenic microenvironment will be crucial to develop effective therapeutics. We have found that tumor cells directly support OC formation independently of PTH-rP, RANKL, and TNF-alpha secretion. Perhaps more interesting, we have also identified a correlation between a tumor cell phenotype that resists apoptotic stimuli and displays enhanced osteoclastogenic potential suggesting a mechanistic link between susceptibility to apoptosis and capacity to induce OC formation. In this regard, our data suggest NF-kappaB is a key transcription factor regulating both resistance to apoptosis and production of osteoclastogenic factors. We postulate that breast cancer cells, via a NF-(B dependent process, develop an enhanced survival to apoptotic stimuli and express factors which act directly on OC precursors. Without these attributes, cancer cells will be unable to invade bone and thus be more susceptible to clearance by the immune system or chemotherapy. We will test this hypothesis by pursuing the following specific aims. 1. Assess the mechanism of action of tumor cells on OC formation and/or activation in vitro. 2. Decipher intracellular signaling pathways controlling expression and/or secretion of osteoclastogenic factors. 3. Evaluate the role of NF-kappaB activity on osteolysis and bone metastasis in vivo. 4. Characterize a new osteoclastogenic factor produced by breast cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA100095-02
Application #
6785537
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$134,460
Indirect Cost
Name
Northshore University Healthsystem Research Institute
Department
Type
DUNS #
154538107
City
Evanston
State
IL
Country
United States
Zip Code
60201
Metkar, Sunil S; Menaa, Cheikh; Pardo, Julian et al. (2008) Human and mouse granzyme A induce a proinflammatory cytokine response. Immunity 29:720-33