Transformation of breast cells by truncated neurokinin-1 receptor is secondary to activation by preprotachykinin-A peptides.
Breast cancer remains the cancer with the highest mortality among women in the United States. Peptides derived from the oncogenic Tac1 gene (full transcript: betaPPT-A) stimulate the proliferation of breast cancer cells (BCCs) via seven-transmembrane G protein-coupled neurokinin 1 (NK1) and NK2 receptors. The NK1 gene could generate full-length (NK1-FL) and truncated (NK1-Tr) transcripts. NK1-Tr lacks 100 residues in their cytoplasmic end, could couple to G proteins, and shows reduced efficiency with respect to internalization and desensitization. This study reports on a role of NK1-Tr in the transformation of nontumorigenic breast cells, and investigates whether Tac1 expression is linked to the generation of NK1-Tr. Western blots and Northern analyses showed coexpressions of NK1-Tr and NK1-FL in BCCs (cell lines and primary cells from patients with different stages of breast cancer). Stable transfections of betaPPT-A or NK1-Tr expression vectors in nontumorigenic cells showed each induces the expression of the other, consequently resulting in a transformed phenotype. Analyses with microarrays indicate similar patterns of cytokine production by NK1-Tr transfectants and BCCs, but not NK1-FL transfectants. These observations indicate tumor-promoting properties by NK1-Tr, but not NK1-FL. Overall, the oncogenic property of Tac1 in breast cells involves concomitant expression of NK1-Tr and vice versa, consequently leading to the production of cytokines with growth promoting functions.
Patel
Hiral J
HJ
Department of Medicine and Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
Ramkissoon
Shakti H
SH
Patel
Prem S
PS
Rameshwar
Pranela
P
D000328:Adult; D000368:Aged; D015152:Blotting, Northern; D015153:Blotting, Western; D001940:Breast / Q000166:cytology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003001:Cloning, Molecular; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D011498:Protein Precursors / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D015320:Tachykinins / Q000378:metabolism*
D016207:Cytokines; D017931:DNA Primers; D011498:Protein Precursors; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; C044206:preprotachykinin