Abstract BL-1: Brinker Award Lecture: How Does HER2 Contribute to Breast Cancer Progression?

Abstract HER2 (also called NEU and ERBB2), a receptor tyrosine kinase frequently overexpressed in breast cancer, is one of the most oncogenic kinases of the human kinome. Multiple mechanisms contribute to the transforming potential of HER2. Although HER2 is structurally similar to the receptors for EGF (EGFR) and neuregulins (ERBB3 and ERBB4), the cytoplasm-facing kinase domain of HER2 is characterized by relatively high basal activity, and unlike the ectodomains of EGFR and ERBB3/ERBB4, HER2?s extracellular part cannot bind any known growth factor with high affinity. Nevertheless, HER2 acts as the preferred partner of the other three receptors, and the heterodimers it forms display not only high kinase activity but also increased binding affinity toward a broad spectrum of growth factors. In addition, HER2-containing heterodimers typically interact with a relatively wide set of cytoplasmic effector proteins, such as the phosphoinositol 3-kinase and SHC, which recruits the mitogen-activated protein kinase pathway. The collective outcome of these functional features translates to prolonged and enhanced signaling capacity. One way to comprehend HER2 is offered by the evolutionary history of the family of receptor tyrosine kinases. Accordingly, HER2 and EGFR share a common precursor, but genome duplications denied a growth factor from HER2, and in parallel inactivated the catalytic function of ERBB3, to achieve a layered signaling network, whose autonomy and steady state are maintained by a dense web of feedback regulatory loops. In line with this scenario, HER2 cannot signal in isolation, but requires an activating growth factor receptor. Once recruited, HER2 enables evasion of negative feedback regulation, such as receptor ubiquitination and intracellular degradation: Unlike homodimers of EGFRs, which are targeted to lysosomes for degradation, HER2-containing heterodimers are targeted to a recycling pathway that replenishes the surface pool of HER2 molecules and further prolongs signaling. In-depth understanding of HER2?s oncogenic functions holds promise for therapy of a fraction of breast cancer patients. For example, the relatively high basal activation of the kinase domain means that HER2 relies on a chaperone called HSP90, hence blocking HSP90 might retard HER2-overexpressing tumors. Likewise, it is predictable that agents able to block either recycling of HER2 or its ability to form heterodimers, would curtail tumor growth. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr BL-1.