Triple-negative breast cancer (TNBC) is highly aggressive and is associated with poor clinical outcomes. TNBC is a major cause of death among breast cancer patients; and is the only subtype of breast cancer that is still lacking effective prevention and therapeutic options. Development of novel preventive or therapeutic approach for TNBC is an important task. The priority area of this research project is on women Veteran’s health, in particular, on women Veterans with TNBC. To assist in this unmet medical need, we propose to pharmacologically target Interleukin 6 (IL-6) and cyclin-dependent kinases (CDK)4/6 pathways simultaneously; because IL-6 and CDK4/6 pathways’ co-activation is enriched in TNBC compared to other breast cancer subtypes. The co-activation is also associated with a shortened time to develop metastasis. Multiple literatures have reported that IL-6 signaling could confer resistance to anti-cancer drugs; and a report suggests that one of the mechanisms of resistance to CDK4/6 inhibitors in breast cancer cells is the activation of IL-6/STAT3 pathway. In addition, our preliminary results show that CDK4/6 inhibitor abemaciclib further induces IL-6 levels in TNBC cells, which could potentially make abemaciclib-treated TNBC cells more resistance to abemaciclib. Therefore, co-activation of IL-6 in TNBC with CDK4/6, could potentially compromise the efficacy of CDK4/6 inhibitors and provide strong rationale to co-target IL-6 and CDK4/6 pathways for effective TNBC preventive therapy. Currently, no small molecule IL-6 drugs are available in clinical trials. To target IL-6 signaling in TNBC for preventive therapy, we repurposed a FDA-approved orally bioavailable drug bazedoxifene as a novel inhibitor of the IL- 6/GP130 signaling. Bazedoxifene is marketed as DUAVEE (bazedoxifene with conjugated estrogens) for preventing postmenopausal osteoporosis. To target CDK4/6 in TNBC, we propose to test abemaciclib (Trade Name: Verzenio), which is one of the most potent CDK4/6 small molecule inhibitors. Abemaciclib has been approved by FDA for the treatments of hormone receptor positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. Our preliminary data indicate that bazedoxifene and abemaciclib combination synergistically inhibited TNBC cell viability in vitro and significantly suppressed tumor growth in vivo. In addition, preliminary results observed that bazedoxifene and abemaciclib combination prevented liver metastasis in orthotopic tumor model after the primary tumors were removed. Our central hypothesis is that dual inhibition of the IL-6 and CDK4/6 pathways by bazedoxifene and abemaciclib combination is an effective approach to prevent TNBC from further progression by suppressing tumor growth and preventing tumor metastasis and tumor recurrence. We will test the central hypothesis by three specific aims: (1) Evaluate the activity of bazedoxifene and abemaciclib combination in preventing TNBC tumor ...