Our findings provide new insights into the molecular mechanisms underlying chemoresistance in BC: (1) SRGN is overexpressed in chemoresistant cells, culture medium from chemoresistant cells and serum from BC patients with poor response to chemotherapy; (2) extracellular SRGN protein interacts with ITGA5 to activate FAK/CREB/YAP signaling; (3) YAP enhances SRGN expression dependent on TEAD1 to form a feed-forward circuit; and (4) YAP interacts with RUNX1 to upregulate HDAC2 expression to mediate chemoresistance (Fig. 8). Here, RUNX1 is linked to breast cancer.