Fig. 10
Proposed mechanism of action of EDPO on ERα+ and triple-negative breast cancer (TNBC) based on experimental and literature data. (A): Antiproliferative effect against ERα+ breast cancer cells. Estrogen signaling drives G1/S transition by inducing Cyclin D1 and c-Myc, ultimately activating cyclin–CDK complexes to inactivate pRB and release E2F1, while simultaneously suppressing the p53–p21 axis through the induction of MDM2. EDPO may counteract this pathway by blocking ERα-driven transcription, reducing CDK activity, stabilizing p53, and restoring checkpoint control. (B): Antimetastatic effect against ERα+ breast cancer cells. ERα promotes migration via non-genomic signaling: estrogen–ERα activates G-proteins and c-Src, leading to PIP3 generation, FAK-mediated adhesion turnover, and Cdc42/Arp2/3-driven actin remodeling. This cascade reorganizes the cytoskeleton to enhance motility. EDPO is proposed to inhibit this ER-dependent pathway, thereby suppressing cell migration. (C): Antitumor effect against TNBC cells. Estrogen-induced dual inhibitory action on CTLs through the mobilization of MDSCs and direct blockade of autocrine IL-2 signaling. EDPO is suggested to counteract the effects of E2, thereby shifting the tumor microenvironment toward a pro-immunogenic state and impairing tumor growth. E2: 17β-estradiol; EDPO: [(3-methoxy-17-oxo-13α-estra-1,3,5(10)-trien-16α-yl)methyl]diphenylphosphine oxide; ERα: estrogen receptor alpha; MDM2: murine double minute 2; pRb: retinoblastoma protein; PI3K: phosphoinositide 3-kinase; FAK: focal adhesion kinase; PIP2: phosphatidylinositol 4,5-bisphosphate; PIP3: phosphatidylinositol 4,5,6-trisphosphate; N-WASP: neural Wiskott-Aldrich syndrome protein; Arp2/3: actin related protein 2/3; MPC: myeloid progenitor cell; MDSC: myeloid-derived suppressor cell; CTL: cytotoxic T-lymphocyte; IL-2: interleukin-2; GrB: granzyme B; PRF1: perforin-1; INFγ: interferon-γ. Figures were created in Inkscape v1.4.2 (https://inkscape.org/). Cell membrane image provided by Servier Medical Art (https://smart.servier.com/smart_image/cell-membrane-13/), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).
