Acquired resistance to endocrine treatments is associated to tumor-specific molecular changes in patient-derived luminal breast cancer xenografts
Menée à l'aide de deux xénogreffes de tumeurs luminales du sein, cette étude met en évidence différents mécanismes de résistance à une hormonothérapie
Purpose: patients with luminal breast cancer (LBC) often become endocrine-resistant over time. We investigated the molecular changes associated with acquired hormono-resistances in patient-derived xenografts of LBC. Experimental design: Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine therapies (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by western blot and immunohistochemistry and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays. Results: HBCx22 TamR xenograft was cross-resistant to several hormono-therapies, while HBCx22 OvaR and HBCx34 TamR exhibited a treatment specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus didn't restore the response to tamoxifen in TamR xenografts. By contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between ER and PI3K pathways. Expression of several ER-controlled genes and ER co-regulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormono-resistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death and cell survival. Conclusions: PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated to specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacological interventions.