Discovery of new therapy targets in HER2-positive breast cancer using a transposon mutagenesis screen

A significant portion of breast cancers remain incurable due to high-risk molecular changes, such as overproduction of HER2 protein. HER2-enhanced breast cancers (HEBC) grow fast, spread early and often relapse quickly when treated. Currently, the only useful approach to slow down HEBC is by inhibiting HER2, which is believed to be a dominant “driver” of these tumours. However, HER2-inhibitory drugs fail to suppress over 70% of HEBC, which are either natively resistant or adapt gradually to become HER2-independent. These facts suggest that HER2-independent mechanisms also contribute significantly to aggressive features of HEBC, including therapy resistance and the propensity to spread into various organs that are directly linked to patient death. Furthermore, an intact immune system has been recently indicated critical to counteract progressive HEBC. So better understanding these mechanisms is fundamentally important to enrich knowledge of HEBC biology and further potentiate better treatment.

With a view to improving HEBC treatment and outcome, our research aims to uncover alternative factors that stimulate growth and spread of HEBC cells by using the latest cutting-edge technologies in molecular cancer research. Additional research focuses include systematic investigation of mechanisms conferring resistance to anti-HER2 therapies or those exploited by tumours to mislead the immune system. Because the targeted disease traits are directly responsible for patient death and inferior quality of life, our discoveries are expected to provide new answers to the clinically critical questions in HEBC, which could be translated into more efficacious therapies. Further, the new methodologies introduced by this research will benefit other breast cancer research.