Simultaneous multi-organ metastases from chemo-resistant triple-negative breast cancer are prevented by interfering with WNT-signaling

Authors

Iram Fatima, University of Tennessee Health Science Center
Ikbale El-Ayachi, University of Tennessee Health Science Center
Hilaire C. Playa, University of Tennessee Health Science Center
Jackelyn A. Alva-Ornelas, Beckman Institute
Aysha B. Khalid, University of Tennessee Health Science Center
William L. Kuenzinger, University of Tennessee Health Science Center
Peter Wend, David Geffen School of Medicine at UCLA
Jackelyn C. Pence, University of Tennessee Health Science Center
Lauren Brakefield, University of Tennessee Health Science Center
Raisa I. Krutilina, University of Tennessee Health Science Center
Daniel L. Johnson, University of Tennessee Health Science Center
Ruth M. O’regan, University of Wisconsin School of Medicine and Public Health
Victoria Seewaldt, Beckman Institute
Tiffany N. Seagroves, University of Tennessee Health Science Center
Susan A. Krum, University of Tennessee Health Science Center
Gustavo A. Miranda-Carboni, University of Tennessee Health Science Center

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.

Publication Title

Advanced Biosystems

Recommended Citation

Fatima, I., El-Ayachi, I., Playa, H., Alva-Ornelas, J., Khalid, A., Kuenzinger, W., Wend, P., Pence, J., Brakefield, L., Krutilina, R., Johnson, D., O’regan, R., Seewaldt, V., Seagroves, T., Krum, S., & Miranda-Carboni, G. (2017). Simultaneous multi-organ metastases from chemo-resistant triple-negative breast cancer are prevented by interfering with WNT-signaling. Advanced Biosystems, 1 (9) https://doi.org/10.1002/adbi.201700056