Early detection of breast cancer and new treatments have now put the 5 year survival rate of patients above 99% and virtually all breast cancer deaths are the result of distal metastases, thus preventing metastasis and recurrence is of great clinical importance. The overall goal of this work is to address whether sympathetic nervous system (SNS) activation induced by chronic stress or depression in breast cancer patients contributes to bone metastasis, recurrence and survival. Clinical evidence and experimental data accumulated in our laboratory, using two mouse models of cancer metastasis to bone, support this hypothesis. Our data also point to osteoblast-derived cytokines RANKL and IL6 as a crucial factor promoting the colonization of cancer cells in the bone microenvironment in response to SNS activation, in addition to their effect on osteoclastogenesis and osteolysis. We propose in this application to characterize the cellular and molecular mechanisms underlying these SNS effects (Aim 1 and 2) and to address whether ?-blockers and RANKL blockade have beneficial effects on bone metastasis and survival in preclinical mouse models characterized by endogenous sympathetic activation (Aim 3).

Public Health Relevance

The studies in this proposal will determine in mouse pre-clinical models whether sympathetic nervous system activation, which is linked to psychosocial conditions associated with poor survival in breast cancer patients, is a critical regulatory component of the bone microenvironment and one of the determinants that control the colonization of breast cancer cells in bone.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168717-02
Application #
8637019
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Woodhouse, Elizabeth
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$313,989
Indirect Cost
$112,714
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Elefteriou, Florent; Campbell, Preston; Ma, Yun (2014) Control of bone remodeling by the peripheral sympathetic nervous system. Calcif Tissue Int 94:140-51