Targeting triple-negative breast cancer by conversion into HER2-positive cancer: A novel therapeutic approach.

Abstract

e11534 Background: Triple negative breast cancer (TNBC) is defined by the lack of estrogen-receptor alpha (ERα) and progesterone receptor (PGR) expression as well as absence of human epidermal growth factor receptor2 (HER2/neu) overexpression. This type of breast cancer is characterized by a poor prognosis and significantly reduced survival rate compared to other BC subtypes. This is mostly due to the lack of targeted agents like endocrine or anti HER2 targets. Breast cancers which overexpress HER2 are usually treated by chemicals targeting HER2; either by blocking the extracellular domain through trastuzumab or the intracellular domain through the small molecule lapatinib. Both therapeutics lead to inhibition of downstream pathways like MAPK and PI3K, resulting in increased apoptosis as well as reduced proliferation. Methods: We hypothesize that downstream effects might be induced in TNBC cells when HER2 is artificially overexpressed and cells get treated as HER2 positive cells. Therefore, triple negative breast cancer cell lines were transfected with HER2. These cells were treated with anti-HER2 agents. Molecular analyses will demonstrate whether transfection with HER2 will yield a HER2 positive breast cancer phenotype in that all downstream signaling mechanisms act similarly to a priori HER2 positive cells. Results: Preliminary experiments suggest that proliferation of TNBC cells transfected with HER2 does not change significantly. Treatment with HER2-blocking antibody trastuzumab leads to significant decrease of proliferation in HER2 transfected, initially triple negative MDA-MB-231 breast cancer cells. Only a moderate decrease in proliferation was observed when lapatinib, a molecule directed against both EGFR and HER2, was used in both MDA-MB-231 wildtype and HER2-transfected cell lines. Conclusions: We surmise that firstly, conversion of cancer might become a clinical tool to treat cancer of poor prognosis and secondly that our results might shed light on future therapeutic approaches e.g. small molecule compound screening for endogenous HER2 reactivation / overexpression and subsequent targeted treatment of triple negative breast cancers.