Two potential mechanisms support this: First, the level of ER expression is likely to correlate with the ability of bortezomib to mediate its synergistic effect, as previously shown in preclinical models.21 As the threshold for the induction of the proapoptotic unfolded protein response requires a minimum level of accumulation of protein aggregates, it is likely that this threshold cannot be reached in breast cancers that express low ER levels. This evidence concerns the gene ESR1 and breast cancer.