Simultaneous Multi-Organ Metastases from Chemo-Resistant Triple-Negative Breast Cancer Are Prevented by Interfering with WNT-Signaling

Abstract

Triple-negative breast cancers (TNBCs), which lack specific targeted therapy options, evolve into highly chemo-resistant tumors that metastasize to multiple organs simultaneously. We have previously shown that TNBCs maintain an activated WNT10B-driven network that drives metastasis. Pharmacologic inhibition by ICG-001 decreases β-catenin-mediated proliferation of multiple TNBC cell lines and TNBC patient-derived xenograft (PDX)-derived cell lines. In vitro, ICG-001 was effective in combination with the conventional cytotoxic chemotherapeutics, cisplatin and doxorubicin, to decrease the proliferation of MDA-MB-231 cells. In contrast, in TNBC PDX-derived cells doxorubicin plus ICG-001 was synergistic, while pairing with cisplatin was not as effective. Mechanistically, cytotoxicity induced by doxorubicin, but not cisplatin, with ICG-001 was associated with increased cleavage of PARP-1 in the PDX cells only. In vivo, MDA-MB-231 and TNBC PDX orthotopic primary tumors initiated de novo simultaneous multi-organ metastases, including bone metastases. WNT monotherapy blocked multi-organ metastases as measured by luciferase imaging and histology. The loss of expression of the WNT10B/β-catenin direct targets HMGA2, EZH2, AXIN2, MYC, PCNA, CCND1, transcriptionally active β-catenin, SNAIL and vimentin both in vitro and in vivo in the primary tumors mechanistically explains loss of multi-organ metastases. WNT monotherapy induced VEGFA expression in both tumor model systems, whereas increased CD31 was observed only in the MDA-MB-231 tumors. Moreover, WNT-inhibition sensitized the anticancer response of the TNBC PDX model to doxorubicin, preventing simultaneous metastases to the liver and ovaries, as well as to bone. Our data demonstrate that WNT-inhibition sensitizes TNBC to anthracyclines and treats multi-organ metastases of TNBC.

Targeting IL-3Rα on tumor-derived endothelial cells blunts metastatic spread of triple-negative breast cancer via extracellular vesicle reprogramming

“…3f). It has been shown that the Wnt/β-catenin network correlates with high metastatic TNBC behavior 39,40 . Therefore, metastases generated from primary tumors were evaluated.…”

Paeoniflorin Sensitizes Breast Cancer Cells to Tamoxifen by Downregulating microRNA-15b via the FOXO1/CCND1/β-Catenin Axis

“… 35 ICG-001, an inhibitor of β-catenin diminished the proliferation of MDA-MB-231 cells by synergizing with cisplatin and doxorubicin. 36 β-catenin, the essential factor of the canonical Wnt signaling, was increased in Tam-resistant BC cell lines, while the inhibition of β-catenin by XAV939 partially reversed Tam resistance by its impact on the cell cycle by lowering the expression of β-catenin and β-catenin-modulated downstream targets such as CCND1. 37 Moreover, CCND1 has been proposed to accelerate binding between β-catenin and Nanog in the nucleus, thus facilitating cervical carcinoma cell colony formation.…”

Targeting Wnt Signaling in Endometrial Cancer

“…Several studies have been published in the last decade that correlate changes in Wnt ligands, receptors, gatekeepers, and downstream effector molecules to almost every type of human tumor. Dysregulation of both canonical and noncanonical Wnt signaling has been shown in numerous cancers [ 16 , 22 , 37 , 54 , 58 , 59 , 60 , 61 , 62 , 63 ]. Table 1 lists reports of Wnt pathway alterations in numerous tumor types.…”