Breast cancer has a predilection for metastasis to the bone marrow. The preprotachykinin-I (PPT-I) gene has a central role in the early migration of breast cancer cells into the bone marrow, making this organ a latent repository of the cancer cells. This study investigated whether the invasive and metastatic potential of breast cancer cells correlate with the expression of the PPT-I gene and the receptors for its peptides, neurokinin-1 (NK-1) and NK-2. The studies compared cells that are non-tumorigenic (MCF12A), low metastatic and invasive potential (MCF7), and sublines of MCF with increased invasive and metastatic potential (LCC1 and LCC2). LCC2, but not LCC1 is tamoxifen resistant. Quantitative RT-PCR showed increased expression of PPT-I, NK-1 and NK-2 mRNA LCC1 and LCC2. MCF7 required stimulation by phorbol ester for NK-1 induction. The levels of NK-2 mRNA were significantly increased in LCC2. Clonogenic assays with specific receptor antagonists showed a predominant role for NK-2 in the proliferation of both LCC1 and LCC2. While the growth rate of LCC1 and LCC2 were similar, the latter showed increased migration. Use of a nude mouse model confirmed higher metastatic potential of LCC2, including increased migration to regions of the endosteum. Overall, these studies show a correlation between three neuroendocrine-related genes: PPT-I, NK-1 and NK-2 and the metastatic potential of specific breast cancer cells. These cells provide a model for future studies on bone marrow metastasis.