Abstract 653: Stat3 as a molecular signature and therapeutic target for inflammatory breast cancer

Inflammatory breast cancer (IBC) is the most aggressive and lethal of all breast cancers. There is little known about the molecular signatures of IBC with the exception that these breast cancers commonly over-express E-cadherin and Rho C GTPase and exist as tumor emboli within dermal lymphatics. In addition, IBC tumor emboli exhibit characteristics of tumor initiating cells, i.e., cancer stem cells. Another interesting characteristic of IBC tumors is their ability to undergo vasculogenic mimicry, forming tube-like structures that abrogate the need of this very aggressive tumor type to induce the development of angiogenic endothelium. In vitro under low adherence culture conditions, IBC cells readily form tumor spheroids that contain ”label retaining” cells and exhibit self-renewal. In addition, when cultured as tumor spheroids in 3 dimensions, they express high levels of the phosphorylated form of the signal transducer and activator of transcription 3 (phospho-stat3), recently shown to regulate survival of embryonic stem cells. From a panel of newly developed novel stat3-targeted peptidomimetics, we found that the lead compound, designated as PM-73G, inhibited phospho-stat3, which was associated with blockade of the robust invasion, anchorage independent growth in soft agar and vasculogenic mimicry exhibited by IBC tumor cells without a significant anti-proliferative effect. Using array-based PCR and protein analysis, we found a specific pattern of inhibition of genes/proteins within the Jak/Stat pathway by PM-73G. Results of comparative studies using both PM-73G and stat3 shRNA demonstrate a role for stat3 in maintenance of the cancer stem cell phenotype exhibited by IBC tumor spheroids. Taken together, these studies suggest that stat3 may serve both as a molecular signature of IBC and as a target for development of effective therapeutics for this lethal form of breast cancer that contain tumor cells exhibiting a cancer stem cell phenotype. (Funded by The Susan G. Komen For The Cure Promise Grant KGO 81287 (FMR), The State of Texas Rare and Aggressive Breast Cancer Fund (FMR), NIH NCI CA096652 (JSM) and Center for Targeted Therapy at The University of Texas M.D. Anderson Cancer Center and the Texas Institute for Drug and Diagnostic Development at The University of Texas, Austin. (FMR & JSM). 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 653.