ESR1 and breast cancer: MCF-7 human breast cancer cells transfected with a full-length cDNA of the HER2 oncogene or treated with ectopic heregulin (HRG; the HER-3/-4 ligand that transactivates HER2) lose E2 dependence.32, 33, 34 Multiple lines of evidence suggest that differences in E2 responsiveness in these models are not attributable to differences in ERα expression levels but rather to the potential interaction of signal transduction elements that link HER2 to ERα.