Triple-negative breast cancers (TNBC) are basal-like tumors which lack the traditional pharmaceutical targets ER, PR and Her2neu. Most TNBC related deaths occur following metastasis of cancer cells, and development of tumors at secondary sites such as the lungs and bones. Since TNBC lacks ER, PR and Her2neu, toxic non-specific chemotherapeutic agents are administered to these women, who generally present with early metastatic lesions that originate from drug-resistant residual cells, and have poor prognosis. Consequently, novel therapeutic strategies are sought. Luteolin (LU) is a naturally occurring, non-toxic plant compound that has proven effective against several types of cancer, though its effects against cancers of the breast remain unknown. With this in mind we conducted studies, both in vivo and in vitro, to determine whether LU might suppress metastasis of TNBC. In vivo studies were performed using MDA-MB-231 (4175) LM2 cells, a subpopulation of clinically relevant cells (kindly provided by Dr. J. Massagué; Minn et al. Nature. 2005, 436:518-24). MDA-MB-231 (4175) LM2 is a particularly aggressive TNBC breast cancer cell line with a molecular signature preferential for lung metastasis. Herein we report that LU effectively suppressed metastasis of MDA-MB-231 (4175) LM2 cells to lung. Compared with animals given MDA-MB-231 (4175) LM2 cells alone, which developed 67.6 ± 27.1 metastatic lung colonies, treatment with 40 mg/kg LU reduced colony formation to 22.8 ± 3.6 (P = 0.035). Confirmation of the anti-metastatic effect of LU was achieved by inoculating animals with an alternative, less aggressive TNBC cell line, MDA-MB-435. Administration of 20 mg/kg LU to animals treated with MDA-MB-435 cells reduced the number of lung colonies from 14.1 ± 1.6 to 5.3 ± 0.5; P < 0.05. When tumor cells were incubated in vitro with different concentrations (0-50 µM) of LU, we observed a significant dose-dependent reduction in cell viability, induction of apoptosis (P = <0.001), and decreased tumor cell migration. These data suggest that LU suppresses several steps of the metastatic process. Furthermore, relatively low levels (10 μM) of LU significantly inhibited VEGF secretion from tumor cells (P = <0.001), suggesting that the flavonoid has the ability to suppress a potent angiogenic and cell survival factor. In addition, when tumor cells were exposed to either LU or VEGF receptor (KDR) antibody, a similar reduction in TNBC migration potential was observed. This suggests that the anti-tumor actions of LU may, in part, be due to its ability to reduce VEGF levels and block KDR receptor-mediated activity, thereby inhibiting tumor cell migration. These studies demonstrate that the use of LU, a non-toxic, plant derived compound, deserves further investigation as a treatment option for women with TNBC.Supported by a COR award from the College of Veterinary Medicine, and in part by funds from generous donors to the Ellis Fischel Cancer Center, University of Missouri.

Citation Format: Matthew T. Cook, Yayun Liang, Cynthia Besch-Williford, Salman Hyder. Luteolin inhibits metastasis of triple-negative breast cancer cells to the lungs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4914. doi:10.1158/1538-7445.AM2017-4914