Nuclear factor-kappaB is central to the expression of truncated neurokinin-1 receptor in breast cancer: implication for breast cancer cell quiescence within bone marrow stroma.
Breast cancer is a leading cause of mortality among women in the United States. Tac1 and neurokinin-1 (NK1) are involved in autocrine stimulation of breast cancer cells (BCCs). The single NK1 gene produces full-length (NK1-FL) and truncated (NK1-Tr) forms. NK1-Tr mediates malignancy in breast cells. We now report a critical role for nuclear factor-kappaB (NF-kappaB) in the expression of NK1-Tr, but not NK1-FL, in human BCCs. By Western and Northern blot analyses, NK1-FL and NK1-Tr were coexpressed in BCCs but were undetectable in nontumorigenic cells. Loss of repressive activity within the 5' flanking region of the NK1 partly accounts for constitutive expression of NK1 in BCCs but could not account for the presence of NK1-Tr. Transient transfections with dominant-negative and wild-type IkappaB show that activation of NF-kappaB is required for the expression of NK1-Tr. Tac1 gene was linked to the generation of NK1-Tr because its overexpression in BCCs led to the production of multiple cytokines that can activate NF-kappaB to mediate NK1-Tr expression. Studies with Tac1 knockdown BCCs and Tac1-expressing nontumorigenic breast cells verified a role for NF-kappaB in the expression of NK1-Tr. The quiescent phenotype of BCCs on contact with bone marrow stroma was partly explained by decreased NF-kappaB activation and undetectable NK1-Tr. In summary, this study shows a role for NF-kappaB in the expression of NK1-Tr in BCCs, which seems to be reversed by bone marrow stromal cells.
Ramkissoon
Shakti H
SH
Department of Medicine and Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA.
Patel
Prem S
PS
Taborga
Marcelo
M
Rameshwar
Pranela
P
D001854:Bone Marrow Cells / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015536:Down-Regulation; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis* / Q000235:genetics; D017154:Stromal Cells / Q000473:pathology; D014162:Transfection
D016328:NF-kappa B; D018040:Receptors, Neurokinin-1