The HER/ErbB family of receptor tyrosine kinases drives critical responses in 
normal physiology and cancer, and the expression levels of the various HER 
receptors are critical determinants of clinical outcomes. HER activation is 
driven by the formation of various dimer complexes between members of this 
receptor family. The HER dimer types can have differential effects on downstream 
signaling and phenotypic outcomes. We constructed an integrated mathematical 
model of HER activation, and trafficking to quantitatively link receptor 
expression levels to dimerization and activation. We parameterized the model 
with a comprehensive set of HER phosphorylation and abundance data collected in 
a panel of human mammary epithelial cells expressing varying levels of 
EGFR/HER1, HER2 and HER3. Although parameter estimation yielded multiple 
solutions, predictions for dimer phosphorylation were in agreement with each 
other. We validated the model using experiments where pertuzumab was used to 
block HER2 dimerization. We used the model to predict HER dimerization and 
activation patterns in a panel of human mammary epithelial cells lines with 
known HER expression levels in response to stimulations with ligands EGF and 
HRG. Simulations over the range of expression levels seen in various cell lines 
indicate that: i) EGFR phosphorylation is driven by HER1-HER1 and HER1-HER2 
dimers, and not HER1-HER3 dimers, ii) HER1-HER2 and HER2-HER3 dimers both 
contribute significantly to HER2 activation with the EGFR expression level 
determining the relative importance of these species, and iii) the HER2-HER3 
dimer is largely responsible for HER3 activation. The model can be used to 
predict phosphorylated dimer levels for any given HER expression profile. This 
information in turn can be used to quantify the potencies of the various HER 
dimers, and can potentially inform personalized therapeutic approaches.