Abstract LB-213: Acheron augments triple negative breast cancer stem-like cells and exacerbates chemotherapeutic and radiation resistance

Abstract

Abstract Basal-like breast cancers that are negative for clinically important receptors (estrogen, progesterone, and Her2/neu), carry the worst prognosis for patients that are diagnosed with breast cancer. Acheron is a novel protein that was recently demonstrated to be highly expressed in triple-negative basal-like breast cancers. Previous work in our lab has demonstrated that breast cancer cell lines that are engineered to express ectopic Acheron are more invasive, have higher levels of MMP-9 and VEGF, and develop increased tumor burden in vivo in xenografted SCID/beige mice. In order to better understand the role Acheron may play in these basal-like breast cancers, the triple negative breast cancer cell lines MDA 231 and MDA 435 were engineered to express ectopic Acheron. Engineered cells were cultured in serum free media with EGF and FGF to cultivate them as mammary cancer stem-like cells. Relative to empty vector control cells, Acheron-expressing MDA 435 cells demonstrated a greater ability to form acini-like structures in suspension as well as support anchorage independent growth. Cells that were cultivated in basal media with serum were also analyzed for cell adhesion and expression of the laminin adhesion protein CD29 (Beta-I Integrin). Expression of Acheron in either MDA 231 and 435 cells lead to a marked reduction in substrate adhesion on laminin-coated plates relative to controls. Consistent with this observation, Acheron-expressing cells also expressed reduced levels of CD29. FACS analysis for the apoptosis markers Annexin-V binding and propidium iodide exclusion demonstrated that Acheron-expressing cells were 2–3 times less sensitive to the same concentration of the chemotherapeutic drugs: Doxorubicin and docetaxel, and to a lesser extent to ionizing radiation (1.6 fold). In summary, we have extended the analysis of Acheron action in triple-negative basal-like breast cancer cells. We have found that these cells that express ectopic Acheron are more resistant to chemotherapeutic drugs and radiation and have a greater capacity to grow in an anchorage-independent manner. These data support the hypothesis that Acheron expression in triple-negative breast cancers may confer properties that would be anticipated to result in a poorer prognosis. Therefore, Acheron deserves attention and further investigation as a new cancer target in triple-negative basal-like breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-213. doi:10.1158/1538-7445.AM2011-LB-213