Abstract 4268: Breast cancer stem cells play a role in trastuzumab resistance in mouse xenograph models

Abstract

Abstract One of the most significant advances in breast cancer therapeutics has been the development of HER2 targeted therapies for treatment of HER2 overexpressing breast cancer. The use of HER2 inhibitors such as trastuzumab have improved patient outcome in both the adjuvant and advanced setting. However, one-third of HER2-positive tumors do not respond to HER2 targeted agents and resistance may develop in patients with chronic exposure. Nearly 50% of patients who respond to HER2 targeted agents relapse within a year. The mechanism of resistance to HER2 targeted agents is not entirely clear. However, increasing evidence indicates that this resistance may be associated with loss of PTEN (phosphotase and tensin homolog), the gain of function of somatic mutations of PI3KA or truncation of the extracellular domain of HER2. We have recently demonstrated that trastuzumab reduces the cancer stem cell (CSC) population in trastuzumab sensitive but not trastuzumab resistant cell lines. In order to elucidate the mechanisms of trastuzumab resistance we engineered MCF7 cells to overexpress HER2, knockdown PTEN or both. HER2 overexpression or PTEN knockdown increased the proportion of CSC's as assessed by the Aldefluor assay and tumor initiation in NOD/SCID mice. Cell lines with both HER2 overexpression and PTEN knockdown contained a significantly higher proportion of Aldefluor positive (3.2 %) compared to either alteration alone (1.7%, 1.9% respectively and 0.5 % in parental cells). In addition, cells with both PTEN deletion and HER2 overexpression showed several fold increase in their invasive properties in vitro as compared cells with either alteration alone. Furthermore, cells with the combined alterations but not those with either alone were highly metastatic in NOD/SCID mice consistent with the demonstrated role of CSC's in mediating tumor metastasis. Trastuzumab treatment significantly reduced the Aldefluor positive population in HER2 overexpressing cells. In contrasts trastuzumab had no effect on the Aldefluor positive population in cells with both HER2 overexpression and PTEN knockdown. These studies suggest that PTEN deletion renders Her 2 overexpressing MCF7 breast cancers resistant to trastuzumab by regulating the CSC population. Strategies aimed at blocking downstream signaling through PI3K or Akt inhibition may effectively target this important cell population in trastuzumab resistant tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4268.