Figure 7. PTPN12 Inhibits Proliferation and Survival of TNBCs by Inhibiting Multiple RTKs.

(A) HER2 and PDGFR-β RTKs interact with PTPN12 in TNBC cells. HCC1937 cells expressing PTPN12-N-YFP and individual RTK-C-YFP cDNAs (as indicated) were analyzed for cellular fluorescence using flow cytometry.

(B) Ectopic PTPN12 expression inhibits HER2 and PDGFR-β RTK signaling in TNBC cells. HCC1937 cells engineered with control or PTPN12-cDNA were assessed for PTPN12 expression and levels of phosphorylated HER2 and PDGFR-β by western.

(C) Combined HER family and PDGFR inhibitors suppress proliferation of PTPN12-deficient TNBC cells. HCC1937 cells were cultured ± HER2/EGFR inhibitor lapatinib (1 μM) ± PDGFR inhibitor sunitinib (5 μM) for 8 days. Cell numbers were determined by DAPI cell counting.

(D and E) Combined HER family and PDGFR inhibitors suppress tumorigenicity of PTPN12-deficient TNBC cells. MDA-MB231-LM2 cells were transplanted in the mouse mammary gland and monitored for primary tumor growth in the presence or absence of HER2/EGFR inhibitor (lapatinib) and PDGFR inhibitor (sunitinib) as indicated (n = 10 for each group). Tumor volumes on day 26 postinjection are shown in (D). Tumor growth curves are shown in (E).

(F) Combined HER family and PDGFR inhibitors extend event-free survival of animals harboring PTPN12-deficient TNBC tumors. Animals transplanted with MDA-MB231-LM2 cells (as above) were treated with the indicated inhibitor and monitored for tumor volume. Events are denoted as animals with tumors greater than 1000 mm³. Error bars represent standard error.