Increased expression of preprotachykinin-1 and neurokinin receptors in human breast cancer cells: Implications for bone marrow metastasis

Neuropeptides are implicated in many tumors, breast cancer (BC) included. P reprotachykinin-l (PPT-I) encodes multiple neuropeptides with pleiotropic f unctions such as neurotransmission, immune/hematopoietic modulation, angiog enesis, and mitogenesis, PPT-I is constitutively expressed in some tumors. In this study, we investigated a role for PPT-I and its receptors, neurokin in-l (NK-1) and NK-2, in BC by using quantitative reverse transcription-PCR , ELISA. and in situ hybridization. Compared with normal mammary epithelial cells (n = 2) and benign breast biopsies (n = 21), BC cell lines (n = 7) a nd malignant breast biopsies (n = 25) showed increased expression of PPT-I and NK-I. NK-2 levels were high in normal and malignant cells. Specific NK- I and NK-2 antagonists inhibited BC cell proliferation, suggesting autocrin e and/or intercrine stimulation of BC cells by PPT-I peptides. NK-2 showed no effect on the proliferation of normal cells but mediated the proliferati on of BC cells. Cytosolic extracts from malignant SC cells enhanced PPT-I t ranslation whereas extracts from normal mammary epithelial cells caused no change. These enhancing effects may be protein-specific because a similar i ncrease was observed for IL-6 translation and no effect was observed for IL -1 alpha and stem cell factor. The data suggest that PPT-I peptides and the ir receptors may be important in BC development. Considering that PPT-I pep tides are hematopoietic modulators, these results could be extended to unde rstand early integration of BC cells in the bone marrow, a preferred site o f metastasis. Molecular signaling transduced by PPT-I peptides and the mech anism that enhances translation of PPT-I mRNA could lead to innovative stra tegies for BC treatments and metastasis.