Development of new and improved strategies for triple-negative breast cancer (TNBC) treatment is urgently needed since molecular complexity of TNBC together with therapy-associated side effects and emergence of drug-resistance often limit effectiveness of current therapies. CARP-1/CCAR1 is a ubiquitous, phospho-protein that can induce proliferation and apoptosis through multiple mechanisms. CARP-1 transduces chemotherapy (adriamycin, etoposide, or Iressa)-dependent inhibitory signaling, and co-activates Adriamycin (ADR)-induced p53. CARP-1 also co-activates cell-cycle regulatory anaphase-promoting complex (APC/C) E3 ubiquitin ligase and steroid/thyroid receptors. Here we report that CARP-1 interacts with ERKs, and binds with NEMO (NF-B Essential Modulator; NF-B-activating kinase IKK subunit ). Our preliminary and published studies revealed that ADR induced CARP-1 threonine627 phosphorylation, ERK activation, and canonical NF-B pathway that involved NEMO-CARP-1 binding. Importantly, inhibition of NEMO-CARP-1 binding diminishes NF-B activation (noted by phosphorylation of p65/RelA) by ADR but not by TNFα, interleukin (IL)2, or EGF. Further, SNI-1, a novel SMI of NEMO-CARP-1 binding, enhances ADR or Cisplatin inhibition of TNBC cells, diminishes levels of genotoxic stress (ADR or Cisplatin)-induced pro-inflammatory cytokines TNFα and IL8. SNI-1 enhances TNBC growth suppression by ADR or Cisplatin in vivo in 4T1 syngeneic tumor model. Hypothesis: DNA Damage-inducing drugs (ADR, Cisplatin) activate CARP-1-mediated canonical NF-B and ERK pathways. The rationale for this hypothesis include our preliminary and published studies that indicate inhibition of therapy-induced, canonical NF-B activation by disruption of NEMO-CARP-1 binding enhances efficacy of ADR and Cisplatin in vitro and in vivo. Moreover, ADR also induces CARP-1 phosphorylation and, since genotoxic therapy also activates ERKs, targeting of NEMO-CARP-1 binding together with ERK inhibitors will result in greater tumor suppression by ADR or Cisplatin. Thus, targeting of CARP-1/NEMO binding could permit us to overcome chemo-resistance in TNBCs without affecting other central functions of NF-B induced by TNFα, IL2, and/or EGF signaling necessary for host tissue homeostasis. We will conduct following three aims to test our hypothesis. Aim 1: To define role of CARP-1 in genotoxic chemotherapy-induced canonical NF-B survival pathway. SNI-1 inhibits therapy-induced NEMO phosphorylation. We will elucidate how SNI-1 inhibits DNA damage-induced, NEMO phosphorylation and canonical NF-B pathway. Aim 2: To investigate mechanism(s) by which CARP-1 interacts with ERKs. We will determine how targeting of ERKs in combination with SNI-1 enhances efficacy of genotoxic chemotherapy. Aim 3: To demonstrate targeting of CARP-1/NEMO-dependent canonical, NF-B signaling by water-soluble SNI-1 alone or coupled with targeting of ERKs by therapeutics currently in clinical trials/use, will result in superior T...