Abstract
Nerve growth factor (NGF) is known to exert a mitogenic effect on human breast cancer cells through proto-TrkA activation. Reverse transcriptase-PCR analysis of proto-TrkA expression in human breast carcinoma specimens and cell lines revealed trkA transcript in 12 of 14 human breast carcinoma specimens and in all of four cell lines tested. While cytofluorimetric and Western blot analysis indicated proto-TrkA expression in three of the four cell lines, NGF stimulated growth in only two of the three positive cell lines. Inhibition of NGF-induced MAPK activation by an antibody directed against the extracellular domain of TrkA but not by an inhibitor of TrkA phosphorylation demonstrated the requirement of NGF binding but not of proto-TrkA kinase activity for MAPK activation, suggesting the recruitment of another kinase for transmission of the mitogenic signaling. Indeed, NGF induced tyrosine phosphorylation and stimulated kinase activity of p185(HER2), a kinase receptor of the HER family. A TrkA phosphorylation inhibitor did not affect this activation. Moreover, the two receptors were coprecipitated by antibodies directed against proto-TrkA and p185(HER2). Down-modulation of p185(HER2) expression in a breast carcinoma line transfected with a construct containing an anti-p185(HER2) antibody sequence and expressing proto-TrkA impaired NGF-induced MAPK activation and proliferation. Together these data show that in cells expressing low levels of TrkA such as breast carcinoma cells, NGF must recruit other overexpressed receptors such as p185(HER2) in order to generate a biological signal that can induce breast cancer cell growth.
Highlights
The development and progression of breast cancer is a multifactorial process that includes the activation of oncogenes and loss of tumor suppressor genes and other genetic disruptions [1]
We analyzed the expression of the high affinity nerve growth factor (NGF) receptor in breast carcinoma cell lines and in human breast carcinoma specimens to determine the molecules involved in NGF-induced signaling, in particular those that cooperate with other tyrosine kinase receptors at the cell surface, such as p185HER2, in signal transduction
The present study demonstrates that NGF-induced activation of breast carcinoma cells growth requires co-operation between the proto-TrkA receptor and p185HER2 in assembling the signal transduction machinery
Summary
The development and progression of breast cancer is a multifactorial process that includes the activation of oncogenes and loss of tumor suppressor genes and other genetic disruptions [1]. All of the four cell lines tested and 12 of 14 human breast carcinoma specimens (Fig. 1a) expressed the proto-trkA transcript.
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