Abstract 3092: Redirection of human HER2-positive breast cancer cells

Abstract

Abstract Breast cancer is the most common form of cancer among women, affecting one eigth of the female population. While advances in clinical management and therapeutic modalities have been achieved, serious limitations in the improvement of outcomes after the diagnosis remain, largely due to the complexity of the underlying biology. Studying the mechanism that makes cancer cells tumorigenic and how they can lose the ability to cause malignant formations is the first step towards understanding complex mechanisms of this disease. The normal mammary microenvironment can redirect cells to assume a normal mammary epithelial phenotype. This phenomenon also applies to tumorigenic cells; cancer cells lose their tumor-forming capacity and differentiate, assuming a normal, non-tumorigenic phenotype. This phenomenon has been termed “cancer cell redirection.” Comparing cells that went through this transformation with original cancer cells, features that identify tumorigenic activity can be acknowledged. We have established an in vitro model of cancer cell redirection, in which HER2+ breast cancer cells are grown alone or in co-culture with normal human breast epithelial cells. The ratios of cells used in co-cultures, 1:1 and 1:50 (cancer: normal) were previously established through in vivo and in vitro studies. Redirection was confirmed by immunostaining. The metric used to determine cancer cell redirection was the absence of receptor tyrosine kinase phosphorylation without a change in surface expression of the receptor. HER2 and P-HER2 expression were both present in the HER2+ cancer cells and in the: MCF10A and 1:1 co-cultures. However, HER2 expression was observed in 1:50 co-cultures, but an absence of P-HER2 was noted. Based on attenuation of receptor phosphorylation in the 1:50 co-cultures we can confirm the breast cancer cell redirection, which matches our previous results. Furthermore, alteration of HER2 dimerization patterns in redirected cells were investigated. The capacity of cancer and redirected cells to form tumors was examined with use of mammosphere assay. Formation of mammospheres has correlated to stem cell function and tumor-initiation capacity. The HER2+ breast cancer cell lines formed significantly higher numbers of spheres compared to the non-tumorigenic breast epithelial cells. Mammosphere formation is decreased in redirected cancer cells. Breast cancer stem cells are HER2+ regardless of pathological or genetic classification. This suggests that HER2 expression is not only a target in HER2+ breast cancer but should be targeted in all breast cancers to prevent breast cancer stem cells from recapitulating tumors following treatment. Our data demonstrates that by attenuating activity of HER2 theses cancer cells lose the capacity to form tumors in vivo and lose their cancer phenotype in vitro. Citation Format: Anastasia Frank-Kamenetskii, Julia M. Mook, Brian W. Booth. Redirection of human HER2-positive breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3092.