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. Author manuscript; available in PMC: 2016 Jul 18.
Published in final edited form as: Nat Med. 2016 Jan 18;22(2):194–201. doi: 10.1038/nm.4032

Figure 4. Clinical relevance and potential therapeutic strategy targeting PARP1 and c-Met in TNBC.

Figure 4

(a) Representative images of immunohistochemical staining for pY907-PARP1 and c-Met in tissue microarrays of 77 cases of breast cancer (see Supplementary Table 3). (b) The synergistic effect of inhibiting c-Met and PARP in TNBC cell lines (MDA-MB-231 and HCC1937) was measured by cell viability assay following a 72-hour treatment. Fa, fraction affected. AG, AG014699; ABT, ABT-888; Cri, crizotinib; Ft, foretinib. (c) The synergistic effect of c-Met inhibitor crizotinib and PARP inhibitor AG014699 in MDA-MB-231 cells and HCC1937 cells was measured by soft agar assay following a 4-week treatment. (d) MDA-MB-231 cells were inoculated into the mammary fat pad of nude mice (10 mice per group) on day 0. When the tumor volume reached ~50 mm3, mice were orally administered crizotinib (5 mg/kg), AG014699 (5 mg/kg), or the combination five times per week for 21 days. Tumor volume was measured at the indicated time points. (e) MDA-MB-231 cells were inoculated into the mammary fat pad of nude mice (10 mice per group) on day 0. When the tumor volume reached ~50 mm3, mice were orally administered foretinib (5 mg/kg), ABT-888 (25 mg/kg), or the combination five times per week for 26 days. Tumor volume was measured at the indicated time points. (f) TUNEL, Ki67, and γ-H2AX staining of MDA-MB-231 xenograft tumor tissues after treatment. (g) The synergistic effect of c-Met and PARP inhibition on MCF-7/vector, MCF-7/c-Met wild-type, or MCF-7/c-Met KD cells was measured by cell viability assay following a 72-hour treatment. (h) MCF-7 cells with ectopic expression of c-Met were inoculated into the mammary fat pad of nude mice (10 mice per group) on day 0. When the tumor volume reached ~50 mm3, mice were orally administered crizotinib (5 mg/kg), AG014699 (5 mg/kg), or the combination five times per week for 21 days. Tumor volume was measured at the indicated time points. (i) H1993 cells were injected subcutaneously into the right flank of female nude mice (10 mice per group) on day 0. When the tumor volume reached ~50 mm3, mice were orally administered crizotinib (5 mg/kg), AG014699 (5 mg/kg), or the combination five times per week for 21 days. Tumor volume was measured at the indicated time points. Error bars represent s.d. *P < 0.05, t-test.