Transcriptome profile of s-SHIP expressing breast cancer cells identifies PIERCE1 as a novel drug-resistance gene

Abstract Triple-negative breast cancer is an aggressive subtype of breast cancer that is not sensitive to hormone inhibition. Its treatment is mainly limited to conventional therapies, including neoadjuvant chemotherapy. But the acquisition of drug resistance is a major obstacle to the eradication of the tumor cells, especially the breast cancer stem cells (BCSCs). Using a double-transgenic mouse model 11.5 kb-GFP x C3(1)-Tag, we have previously shown that s-SHIP expression identifies a breast cancer stem cell–related population in primary tumors. To investigate the chemoresistance of s-SHIP/GFP-expressing tumor cells, we used the MAM326 cell line, established from a tumor isolated from these double-transgenic mice. A subset of s-SHIP/GFP+ MAM326 cells, displaying a drug-tolerant stem-related phenotype, exhibited enhanced resistance to various chemotherapy drugs, including paclitaxel and doxorubicin. Transcriptomic analysis revealed that these s-SHIP/GFP+ cells exhibited upregulation of several genes associated with chemoresistance. Furthermore, this analysis highlighted Pierce1 which plays a role in DNA damage response. We showed that Pierce1 was significantly overexpressed in transiently surviving cells treated with paclitaxel and doxorubicin, both in MAM326 cells and in a primary tumoroid model. Overexpression of PIERCE1 in human TNBC SUM159PT cells led to increased resistance to chemotherapy, while its knockdown reduced this resistance. Importantly, clinical data further supported the association of high PIERCE1 expression with poor prognosis and reduced survival in TNBC patients treated with neoadjuvant chemotherapy. This study unveils the potential of PIERCE1 as a therapeutic target for overcoming chemotherapy resistance in breast cancer.