Our observation that the correlation of COX-2 with Akt pathway activation is greatest in ER-negative patients, who also have HER2 positivity, are supported by our previous finding that while PGE2 phosphorylated Akt at Ser473 and GSK-3β at Ser9 in two breast cancer cell lines, the response was considerably stronger in the ER-negative MDA-MB-231 than the ER-positive MCF-7 breast cancer cells. This evidence concerns the gene ESR1 and breast cancer.