Anterior Gradient protein 2 is a marker of tumor aggressiveness in breast cancer and favors chemotherapy-induced senescence escape.

ABSTRACT: Among the different chemotherapies available, genotoxic drugs are widely used. In response to these drugs, particularly doxorubicin, tumor cells can enter into senescence. Chemotherapy-induced senescence (CIS) is a complex response. Long described as a definitive arrest of cell proliferation, we and various groups have shown that this state may not be complete and could allow certain cells to reproliferate. The mechanism could be due to the activation of new signaling pathways. In the laboratory, we study the proteins involved in these pathways and triggering cell proliferation. In this study, we determine a new role for Anterior Gradient protein 2 (AGR2) in vivo in patients and in vitro in a senescence escape model. We used proteomic studies of patients’ samples and cell lines, and also RNA interference to assess the implication of AGR2 in breast cancer and proliferation of senescent cells. First, we identified AGR2, and found that its concentration is higher in the serum of breast cancer patients and that this high concentration is associated with metastasis occurrence. We also observed an inverse correlation between intratumoral AGR2 expression and the senescence marker p16. This observation led us to study AGR2’s role in the CIS escape model. In this model, we found that AGR2 is overexpressed in cells during senescence escape and its loss considerably reduces that phenomenon. Furthermore, we showed that the extracellular form eAGR2 stimulated the reproliferation of senescent cells. The power of proteomic analysis based on the SWATH-MS approach allowed us to highlight the mTOR/AKT signaling pathway in the senescence escape mechanism mediated by AGR2. Analysis of the two signaling pathways revealed that AGR2 modulates RICTOR phosphorylation. All these results show that AGR2 is a breast cancer biomarker and regulates CIS escape via activation of the mTORC2/AKT signaling pathway.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast

DISEASE(S): Breast Cancer

SUBMITTER: Catherine Guette  

LAB HEAD: Olivier Coqueret

PROVIDER: PXD028073 | Pride | 2022-02-15

REPOSITORIES: Pride