Increased Expression of Preprotachykinin-I and Neurokinin Receptors in Human Breast Cancer Cells: Implications for Bone Marrow Metastasis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 1; pp. 388 - 393
• Main Authors: Singh, Deeppreet, Joshi, Deval D., Hameed, Meera, Qian, Jing, Gascón, Pedro, Maloof, Paul B., Mosenthal, Anne, Rameshwar, Pranela
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 04.01.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Benzamides - pharmacology; Biological Sciences; Biopsies; Biphenyl Compounds - pharmacology; Bone marrow; Bone Marrow Cells; Bone Marrow Neoplasms - secondary; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - therapy; Breasts; Cell Division - drug effects; Cell growth; Cell lines; Cells; Cultured cells; Epithelial cells; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; In Situ Hybridization; Messenger RNA; Metastasis; neurokinin receptors; Neurokinin-1 Receptor Antagonists; NK-1 gene; NK-2 gene; Peptides; Piperidines - pharmacology; PPT-I gene; preprotachykinin I; preprotachykinin I receptors; Protein Precursors - genetics; Protein Precursors - metabolism; Receptors; Receptors, Neurokinin-1 - genetics; Receptors, Neurokinin-2 - antagonists & inhibitors; Receptors, Neurokinin-2 - genetics; RNA; Substance P - antagonists & inhibitors; Substance P - metabolism; Tachykinins - genetics; Tachykinins - metabolism; Tumor Cells, Cultured
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.97.1.388

Neuropeptides are implicated in many tumors, breast cancer (BC) included. Preprotachykinin-I (PPT-I) encodes multiple neuropeptides with pleiotropic functions such as neurotransmission, immune/hematopoietic modulation, angiogenesis, and mitogenesis. PPT-I is constitutively expressed in some tumors. In this study, we investigated a role for PPT-I and its receptors, neurokinin-1 (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) and malignant breast biopsies (n = 25) showed increased expression of PPT-I and NK-1. NK-2 levels were high in normal and malignant cells. Specific NK-1 and NK-2 antagonists inhibited BC cell proliferation, suggesting autocrine 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 proliferation of BC cells. Cytosolic extracts from malignant BC cells enhanced PPT-I translation whereas extracts from normal mammary epithelial cells caused no change. These enhancing effects may be protein-specific because a similar increase was observed for IL-6 translation and no effect was observed for IL-1α and stem cell factor. The data suggest that PPT-I peptides and their receptors may be important in BC development. Considering that PPT-I peptides are hematopoietic modulators, these results could be extended to understand early integration of BC cells in the bone marrow, a preferred site of metastasis. Molecular signaling transduced by PPT-I peptides and the mechanism that enhances translation of PPT-I mRNA could lead to innovative strategies for BC treatments and metastasis.