Abstract
Triple-negative breast cancer (TNBC) typically has a worse outcome than other breast cancer subtypes, in part owing to a lack of approved therapeutic targets or prognostic markers. We have previously described an oncogenic pathway in basal-like TNBC cells, initiated by insulin-like growth factor binding protein-3 (IGFBP-3), in which the epidermal growth factor receptor (EGFR) is transactivated by sphingosine-1-phosphate (S1P) resulting from sphingosine kinase (SphK)-1 activation. Oncogenic IGFBP-3 signaling can be targeted by combination treatment with the S1P receptor modulator and SphK inhibitor, fingolimod, and the EGFR kinase inhibitor, gefitinib (F + G). However, the interaction of this treatment with chemotherapy has not been documented. Since we observed nuclear localization of IGFBP-3 in some TNBC tumors, this study aimed to evaluate the prognostic significance of nuclear IGFBP-3 in pre-clinical models of basal-like TNBC treated with F + G and doxorubicin. Orthotopic xenograft tumors were grown in nude mice from the human basal-like TNBC cell lines MDA-MB-468 and HCC1806, and were treated with gefitinib, 25 mg/Kg, plus fingolimod, 5 mg/Kg, 3-times weekly. In some studies, doxorubicin was also administered once weekly for 6 weeks. Tumor tissue proteins were quantitated by immunohistochemistry (IHC). Interaction between doxorubicin and F + G was also studied in proliferation assays in vitro. In both tumor models, tissue staining for IGFBP-3 was predominantly nuclear. Combination of F + G significantly enhanced mouse survival, decreased nuclear IGFBP-3 and Ki67 staining, and increased apoptosis (cleaved caspase-3) staining. Kaplan–Meier survival analysis showed that a high tumor IGFBP-3 IHC score (>median), like a high Ki67 score, was significantly associated with shorter survival time, whereas a high apoptosis score was associated with prolonged survival. Studied in vitro in both cell lines, low-dose doxorubicin that had little effect alone, strongly enhanced the cytostatic effect of low-dose F + G combination. However, in both in vivo models, doxorubicin at maximum-tolerated dose neither inhibited tumor growth when administered alone, nor enhanced the significant inhibitory effect of F + G. We conclude that doxorubicin may not add benefit to the inhibitory effect of F + G unless its dose-limiting toxicity can be overcome. Nuclear IGFBP-3 appears to have potential as a prognostic marker in TNBC and could be evaluated for clinical utility.
Highlights
Breast cancer is recognized as a heterogeneous disease, commonly classified into subtypes on the basis of phenotypic and/or molecular characteristics [1, 2]
insulin-like growth factor binding protein-3 (IGFBP-3) itself, which is abundant in the circulation [14] and in estrogen receptor (ER)-negative breast cancer tissue [24], is a challenging therapeutic target, we showed that IGFBP-3-dependent oncogenic signaling can be successfully targeted by dual therapy with an epidermal growth factor receptor (EGFR) kinase inhibitor and a sphingosine kinase (SphK) inhibitor, giving a highly synergistic inhibitory effect [5, 13]
IGFBP3 is activated by wild-type p53 [49], and, expected to be induced by chemotherapy, we have previously shown that in some Triple-negative breast cancer (TNBC) cell lines with gain-of-function p53 mutations, IGFBP-3 is paradoxically downregulated by DNA-damaging chemotherapeutic drugs [50]
Summary
Breast cancer is recognized as a heterogeneous disease, commonly classified into subtypes on the basis of phenotypic and/or molecular characteristics [1, 2]. Of the breast cancers with absent or very low estrogen receptor (ER) and progesterone receptor (PR), and without overexpression of the human epidermal growth factor receptor-2, known as triple-negative breast cancers (TNBC), about 80% have a basal-like profile, in terms of both gene expression profile [3] and the display of established basal histology markers, such as cytokeratin 5/6 and the epidermal growth factor receptor (EGFR) [4]. There are no established molecular targets or prognostic markers for TNBC, which typically has a worse outcome than other breast cancer subtypes [6]. Our recent pre-clinical studies have revealed an unexpected immune modulator in a murine TNBClike model, with the demonstration that mammary tumors in mice null for insulin-like growth factor binding protein-3 (IGFBP-3) grow 50% smaller than those in wild-type mice and show increased accumulation of CD8+ lymphocytes [8]. In wild-type mice, tumor IGFBP-3 gene expression was positively associated with tumor weight [8], consistent with some clinical studies showing that high IGFBP-3 abundance in breast tumor tissue is associated with high tumor grade [9] and poor prognosis [10, 11]
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