Figure 3.

Biological markers to assess the efficacy of HER TKIs (II): intracrine/nuclear functions of the HER3 ligand heregulin. The intrinsic or acquired ability of breast cancer cells to specifically regulate the expression and/or the subcellular compartmentalization of the human epidermal growth factor receptor (HER)3 ligand heregulin might represent a previously unrecognized mechanism that regulates the efficacy if HER tyrosine kinase inhibitors (TKIs). In one hand, heregulin has been found to promote slow enrichment of HER3 in the cytoplasm/membrane compartments and its deprivation in the nucle(ol)us [23]. This intracrine mechanism of action may significantly increase HER3 membrane expression and, therefore, the HER3 phosphorylation reaction. On the other hand, a 'direct mode' that involves active transport of heregulin to the cell nucleus, and its association with and regulation of target genes or nuclear proteins may add even more complexity to the breast cancer 'HER-TKIs' scenario, because it might bypass the antiproliferative effects of HER-directed TKIs without need for the activation of specific HER receptor tyrosine kinase members and/or HER network-driven activation of downstream signalling cascades [24-28].