Knockout of Heregulin (HRG) Expression Reverts Paclitaxel-Resistance and Promotes Mesenchymal Epithelial Transition (MET) of Triple Negative Breast Cancer Cells.

Abstract

Abstract The growth factor Heregulin (HRG) is expressed in about 30% of breast cancer tumors, and induces tumorigenicity and metastasis of breast cancer cells. We have demonstrated previously that HRG overexpression renders breast cancer cells resistance to the microtubule-interfering agent Taxol, a drug of choice for the treatment of metastatic breast cancer. The mechanism by which HRG induces Taxol resistance is largely unknown. It is also known that triple negative breast cancer tumors do express high levels of HRG and unfortunately they do not respond to HRG. Our studies were aimed at targeting HRG with the goal of achieving a therapeutic target as well as restoring the response to Taxol, while preventing the formation of metastasis. Thus, we knocked-down HRG expression in three different breast cancer cell lines: MDA-MB-23, HS578T and BT549. Our data demonstrates that HRG expression is an absolute requirement for the anchorage-independent growth for triple negative breast cancer cells, since none of the breast cancer cells MDA-MB-231, HS578T and BT549 stable expressing the silencing (shRNA) for HRG, were capable of forming colony in soft agar. Furthermore, these cells, not only no longer were not anchorage-independent were no longer resistant to Taxol, to the contrary the shRNA/HRG cells were exquisitely sensitive to Taxol, to induce growth inhibition and apoptosis. More importantly, we observed that the disorganized structured observed in 3D matrigel culture observed for triple negative cells, was completely abolished once HRG was knockdown and a very organized structure. These characteristics resembled an EMT (epithelial-mesenchymal epithelial transition (MET). This should be deemed a potential target in developing therapies for triple negative breast carcinomas. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1142.