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Breast Cancer Res. 2017 Aug 4;19(1):90. doi: 10.1186/s13058-017-0882-x.

Inhibition of basal-like breast cancer growth by FTY720 in combination with epidermal growth factor receptor kinase blockade.

Author information

1
Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.
2
Present address: Westmead Hospital, Westmead, NSW, 2145, Australia.
3
Patricia Ritchie Centre for Cancer Care and Research, Mater Hospital, North Sydney, NSW, 2065, Australia.
4
Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia. robert.baxter@sydney.edu.au.

Abstract

BACKGROUND:

New molecular targets are needed for women with triple-negative breast cancer (TNBC). This pre-clinical study investigated the combination of the EGFR inhibitor gefitinib with the sphingosine kinase (SphK) inhibitor FTY720 (Fingolimod), aiming to block tumorigenic signaling downstream of IGFBP-3, which is abundantly expressed in basal-like TNBC.

METHODS:

In studies of breast cancer cell growth in culture, proliferation was monitored by IncuCyte live-cell imaging, and protein abundance was determined by western blotting. In vivo studies of mammary tumor growth used two models: orthotopic xenograft tumors derived from three basal-like TNBC cell lines, grown in immune-deficient mice, and syngeneic murine 4T1 tumors grown in immune-competent mice. Protein abundance in tumor tissue was assessed by immunohistochemistry.

RESULTS:

Quantitated by live-cell imaging, the inhibitor combination showed synergistic cytostatic activity in basal-like cell lines across several TNBC molecular subtypes, the synergy being decreased by IGFBP-3 downregulation. Suppression of the tumorigenic mediator CD44 by gefitinib was potentiated by FTY720, consistent with CD44 involvement in the targeted pathway. In MDA-MB-468 and HCC1806 orthotopic TNBC xenograft tumors in nude mice, the drug combination inhibited tumor growth and prolonged mouse survival, although this effect was not significant for the gefitinib-resistant cell line HCC70. Combination treatment of murine 4T1 TNBC tumors in syngeneic BALB/c mice was more effective in immune-competent than immune-deficient (nude) mice, and a relative loss of tumor CD3 (T-cell) immunoreactivity caused by FTY720 treatment alone was alleviated by the drug combination, suggesting that, even at an FTY720 dose causing relative lymphopenia, the combination is still effective in an immune-competent setting. Immunohistochemistry of xenograft tumors showed significant enhancement of caspase-3 cleavage and suppression of Ki67 and phospho-EGFR by the drug combination, but SphK1 downregulation occurred only in MDA-MB-468 tumors, so is unlikely to be integral to treatment efficacy.

CONCLUSIONS:

Our data indicate that targeting IGFBP-3-dependent signaling pathways through gefitinib-FTY720 co-therapy may be effective in many basal-like breast cancers, and suggest tissue IGFBP-3 and CD44 measurement as potential biomarkers of treatment efficacy.

KEYWORDS:

Basal-like breast cancer; FTY720; Gefitinib; IGFBP-3; Sphingosine kinase

PMID:
28778177
PMCID:
PMC5545026
DOI:
10.1186/s13058-017-0882-x
[Indexed for MEDLINE]
Free PMC Article

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