The erbB-2 gene is amplified and overexpressed in approximately one-fourth of breast cancer specimens, and it is overexpressed without gene amplification in an additional 5% to 10% of patients. The repeated observation that erbB-2 overexpression is an indicator of poor prognosis, coupled with the evidence which indicates that erbB-2 has transforming potential both in vivo and in vitro, provide strong evidence that this gene plays a direct and causal role in human breast cancer progression. In studies with both rodent and human breast cancer cells, the principal investigator has repeatedly observed that constitutive activation of erbB-2 is associated with growth factor independent proliferation of the cells. This suggests that overexpression of erbB-2 in breast cancer is a likely mechanism by which cells become autonomous of growth factors for proliferation. Nevertheless, a direct and causal link between overexpression of erbB-2 and growth factor independent proliferation has yet to be established. To examine this, the following studies will be carried out.
Aim 1. To determine if progressive overexpression of erbB-2 in normal human mammary epithelial cells that are strictly growth factor dependent for proliferation results in the gradual acquisition of growth factor independent proliferation. Further, the principal investigator will determine if the level of erbB-2 overexpression determines the extent of growth factor independent proliferation.
Aim 2. To determine the role of a stimulatory ligand in constitutive activation of erbB-2 in cells that overexpress the receptor. It is clear that overexpression of erbB-2 in breast cancer cells yields receptors that are constitutively tyrosine phosphorylated to high levels in the absence of exogenous stimulatory ligand. What is unclear is whether autocrine or juxtacrine activation of these receptors is necessary for this high level activation, or whether receptor overexpression alone is sufficient to yield constitutive activation of these receptors.
Aim 3. To determine the role of erbB-3 in constitutive activation of erbB-2 and growth factor independent proliferation of human breast cancer cells that overexpress erbB-2. It is known that in normal cells, heregulin-induced activation of erbB-2 requires the presence of erbB-3. However, it is not known whether erbB-3 plays a role in erbB-2 activation and signal transduction when erbB-2 is overexpressed or whether erbB-2 acts independently of erbB-3 when the former is expressed to high levels.
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