Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis.
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-1alpha 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.
Singh
D
D
Department of Medicine-Hematology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, USA.
Joshi
D D
DD
Hameed
M
M
Qian
J
J
Gascón
P
P
Maloof
P B
PB
Mosenthal
A
A
Rameshwar
P
P
D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001854:Bone Marrow Cells; D019046:Bone Marrow Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics* / Q000628:therapy; D002455:Cell Division / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D017403:In Situ Hybridization; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000235:genetics*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D013373:Substance P / Q000037:antagonists & inhibitors / Q000378:metabolism; D015320:Tachykinins / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D001549:Benzamides; D001713:Biphenyl Compounds; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011498:Protein Precursors; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; C044206:preprotachykinin; D013373:Substance P; C073839:SR 48968; C066892:CP 96345