Therapeutic potential of RUNX1 and RUNX2 in bone metastasis of breast cancer

Breast cancer (BC) is the leading cause of death among females worldwide. The disease is classified into four molecular subtypes: luminal A, luminal B, overexpressed HER2, and triple-negative (Table 1), according to the Consensus Discussion in St. Gallen 2011. The main treatment options for breast cancer include surgery, radiotherapy, endocrine therapy, chemotherapy, and targeted therapy. Targeted therapy is a specific type of cancer treatment that offers advantages such as precise targeting and fewer side effects compared to other treatments. Endocrine therapy suppresses ovarian estrogen and aromatase conversion of androgens. Current endocrine therapeutic drugs include ovarian function inhibitors zoladex (Goserelin) and enantone (Leuprorelin), aromatase inhibitors anastrozole (Arimidex), letrozole (Femara), exemestane, ER modulators like Tamoxifen and Raloxifane, selective estrogen receptor degrader (SERD) fulvestrant and available cyclin-dependent kinase (CDK) 4/6 inhibitors [1,2]. The functions, effects, and limitations of endocrine therapeutic drugs have been elaborated in Table 2 [3-7]. It is reported that endocrine therapy have side effects on cognition by estradiol. Besides, there are also HER2 targeted therapies, including trastuzumab, pertuzumab, T-DM1, lapatinib, pyrotinib tucatinib, neratinib, and trastuzumab deruxtecan (T-DXd) [8]. Breast cancer may recur despite the use of medications, and drug resistance is progressively revealed. ET’s drug resistance is primarily due to the following two mechanisms. ET resistance can be caused by either ligandindependent, ER-mediated signaling promoting tumor proliferation without hormone, or ER-independent oncogenic signaling bypassing endocrine-regulated transcription pathways [2,9]. However, the mechanisms vary between drugs and must be investigated in greater depth. These pharmaceuticals have beneficial therapeutic effects, but it is also crucial to be aware of the potential adverse effects they may cause such as gastrointestinal toxicity, liver toxicity, thrombocytopenia and interstitial lung disease [10]. Drug resistance is more pronounced due to the metastatic character and high recurrence rate of HER2+ breast cancer [8,10]. Therefore, new molecular targets need to be explored to improve treatment efficacy and reduce drug resistance. Breast cancer is a heterogeneous disease with different subtypes that require distinct treatment approaches. Triple-negative breast cancer (TNBC) is particularly challenging to treat due to a lack of effective therapies beyond chemotherapy [11,12]. However, advancements in molecular medicine have accelerated the discovery of new targeted drugs, such as PARP inhibitors, antibody-drug conjugates, and immune checkpoint inhibitors, that show promise in treating TNBC [11,13]. Despite these approaches, resistance and relapse is still common in the advanced breast cancer patient. Bone metastasis is the most common form of breast cancer metastasis and a major cause of patient mortality. Currently, bisphosphonates and RANK/RANKL inhibitors (denosumab) are the principal drugs used to treat bone metastases, but their effectiveness is limited. Emerging drugs include tissue proteinase K inhibitors, Src inhibitors, transforming growth factor beta blockers, C-X-C motif chemokine receptor 4 (CXCR4) inhibitors, and αvβ3 integrin antagonists, in addition to cabozantinib [14–16]. Although there are several drugs available for treating bone metastases in breast cancer, their efficacy is limited, and there are still significant unmet needs. For example, the RANK/RANKL system sometimes has a negative impact on tumor progression and anti-tumor immunity [17,18]. Furthermore, these drugs primarily target bone metabolism and do not directly affect cancer cells. Thus, new drugs targeting specific molecules and pathways involved in bone metastasis and cancer progression are urgently needed to improve treatment outcomes. Interestingly, RUNX family member is closely associated with cancer [19,20]. RUNX1 is associated with the WNT pathway and overexpressed in invasive breast cancer. Meanwhile, mutations in RUNX1 and its binding partner CBF-β are observed in luminal breast cancer patients [21,22]. On the other hand, RUNX2 is critical for osteoblast differentiation, chondrocyte maturation, and bone formation. It is overexpressed in the breast and interacts with transforming growth factor (TGF), Wnt, and p53. Also, it promotes epithelial-mesenchymal transition (EMT), upregulates extracellular matrix degrading enzymes, subsequently boosting metastatic phenotype and cancer cell invasiveness and metastasis. Furthermore, recent studies have identified the RUNX family of transcription factors as having therapeutic potential