By extensively utilizing TZMB-refractory breast cancer cell lines transduced with diverse phosphovariants of HSP27, our study newly revealed that specific phosphorylation of HSP27 at S15 promoted its S78 phosphorylation and served as key mediator to promote direct interactions that increase the stability of HER2 and protein kinase B (AKT). Here, HSPB1 is linked to breast carcinoma.