Adipose tissue contributes to obesity-associated risk in breast cancer progression. Recent work has demonstrated the involvement of preadipocytes in promoting the induction of breast tumor cell migration and invasion. Neuropeptide Y (NPY) stimulates proliferation of preadipocytes in vitro by the Y1 receptor. NPY receptors are present in almost all primary breast cancers and in lymph node metastases from ER-positive primary cancers. By contrast, the peptide has been shown to inhibit the invasion of certain tumor cells. However, the relative contribution of adipose and NPY to breast tumor survival remains to be determined. Using the highly metastatic ER-negative human breast cancer cell line MDA-MB-231, we found that NPY significantly inhibited cell proliferation, an effect that was reversed by treatment with the Y1-receptor antagonist BIBP-3226 (P<0.05). Breast tumor cells treated with NPY exhibited changes in cell morphology and demonstrated a two-fold increase in early apoptosis. When breast tumor cells were incubated in the presence of conditioned media harvested from 3T3-L1 preadipocytes, NPY enhanced apoptosis. Significantly more breast tumor cells migrated toward the preadipocytes compared to conditioned media alone (P<0.0001), but less in the presence of NPY. In conclusion, it appears that adipose tissue promotes breast tumor survival and migration, while NPY limits its. It will be of interest to determine whether the tumor migration-promoting activity of preadipocytes varies among breast cancer subtypes, and if so, whether it serves as a predisposing factor for breast cancer progression. In addition, the targeting of NPY-Y1 receptors in breast tumors may have a diagnostic and possibly therapeutic value. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1213. doi:10.1158/1538-7445.AM2011-1213