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.
Highlights
Triple-negative breast cancers (TNBC) are an aggressive breast cancer subtype devoid of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor2 (HER2) amplification, and are, unresponsive to targeted therapies such as trastuzumab and anti-estrogen therapies
We showed that ICG-001 targets an auto-regulatory-loop, composed of HMGA2 and EZH2, that is necessary for maintenance of the WNT nuclear components β-catenin/TCF4/LEF-1 to induce gene transcription of WNT10B direct target genes [10]
The ICG-001 effects are specific for TNBC, as exposure of ICG-001 was nontoxic to normal human mammary epithelial cells (HUMEC), and human epithelial breast MCF10A cells, as well as ER+ MCF7 and human epidermal growth factor receptor2 (HER2)+ SKBr3 cell lines
Summary
Triple-negative breast cancers (TNBC) are an aggressive breast cancer subtype devoid of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor2 (HER2) amplification, and are, unresponsive to targeted therapies such as trastuzumab and anti-estrogen therapies. There is evidence that African-American (AA) women diagnosed with TNBC have worse clinical outcomes than women of European-American (EA). The development of novel or repurposed drug therapies is urgently needed to treat highly chemo-resistant metastatic TNBC disease (metTNBC). Metastatic breast cancer (MBC), called stage IV or advanced breast cancer, is the leading cause of worldwide cancer-related deaths among women. ER+ cancers preferentially disseminate to the bone, liver, and brain [3]. MetTNBC preferentially metastasizes to multiple visceral organs, including the liver and lungs, to the brain and, less frequently, to the bone. MetTNBC patients diagnosed with multi-organ metastases do worse and their median survival is about a year [4]. Patients identified by the WNT/β-catenin network classifier have a greater risk of lung and brain metastases in TNBC [5]
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