Sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) genes code for DNA-binding proteins that help regulate cell differentiation, organogenesis, and other developmental processes [21]. The SOX family contains more than 20 members in vertebrates, which are classified into eight groups [21]. SOX transcription factors are involved in cell determination and regulation of cell plasticity in normal cells, but in cancer cells, these processes are abnormally regulated, leading to the promotion of tumor heterogeneity and metastasis [22]. SOX4 contributes to breast cancer metastasis by activating the TGFβ pathway and promoting the expression of EMT inducers [21]. SOX2 expression is positively correlated with tumor size and promotes angiogenesis to enable lymph node metastasis [21, 23]. SOX9 accumulation in the cytoplasm increased proliferation, migration, and invasion, and targeting this gene showed less metastasis [21]. The SOX gene family transcription factors are other potential targets for treatment due to their roles in metastatic processes.

The E26 transformation-specific (ETS) family is a large transcription factor family consisting of 27 ETS genes in humans which can be structurally categorized into 11 subfamilies [24]. The ETS family of transcription factors regulates signaling, development, apoptosis, and metastatic processes [24]. Increased expression of ETS transcription factors has been observed in invasive and metastatic breast tumors and indicates poor prognosis [24]. The ETS family plays a role in breast cancer metastasis by affecting genes such as HER2 and VEGF that are related to steps in the metastatic process such as proliferation, transformation, migration, invasion, anti-apoptosis, and angiogenesis [24]. A subgroup in the ETS family called the PEA3 group is overexpressed in both human and mouse mammary tumors [25]. PEA3 overexpression increases invasion and migration and is positively correlated with HER2/neu expression in 25–30% of HER2-positive breast cancers [24]. ETS1 overexpresses Long Intergenic Non-protein Coding RNA 1016 (LINC01016), suppressing some ubiquitination degradation in breast cancer cells [26]. ETS1 is correlated with invasiveness, EMT, and angiogenesis, and ETS2 is correlated with apoptosis, so these transcription factors also impact breast cancer metastasis through differential regulation of metastatic processes [24].

Yin Yang 1 (YY1) is a transcription factor often upregulated in many cancers, including metastatic breast cancer [27]. YY1 is negatively correlated with the survival of breast cancer patients and positively correlated with cancer stem cell markers such as SOX2, OCT4, BMI1, and NANOG, all of which are related to drug resistance [27, 28]. YY1 regulates BRCA1 and HER2 tumorigenic pathways to promote tumor angiogenesis and metastasis [28]. The main contribution of YY1 to metastatic breast cancer is its ability to increase cancer stem cell qualities in tumors, which helps enable metastasis.

Forkhead box M1 (FoxM1) is a transcription factor that regulates the cell cycle and mitotic spindle formation in normal cell growth and carcinogenesis by promoting cell motility, invasion, EMT, and metastasis [29]. FoxM1 expression is associated with increased tumor size, lymphovascular invasion, and lymph node metastases [29]. FoxM1 has been implicated in each stage of metastasis by promoting EMT, activating the TGFβ pathway, and modulating the extracellular matrix through the regulation of the other genes [29, 30]. Because of the evident role of FoxM1 in all breast cancer stages and in all breast cancer subtypes, it is a promising potential therapeutic target to block [31, 32].

BTB domain and CNC homology 1 (Bach1) is a transcription factor with increased expression in breast cancer cells [33]. Bach1 is a known regulator of heme homeostasis, oxidative stress response, mitochondrial metabolic processes, and the cell cycle [33]. Overexpression of Bach1 promotes migration, invasion, and hypoxia-related pathways [34]. Specifically, in TN breast cancer cells, Bach1 regulates pathways and the expression of genes involved in cellular respiration, affecting the survival of cancer cells [33]. Bach1, like many transcription factors, proves to be a useful target for the treatment and prognosis of metastatic breast cancer.

The sineoculis homeobox homolog (SIX) family of transcription factors has six members which are important to cell proliferation, differentiation, apoptosis, adhesion, and migration [35]. One study found that expression levels of SIX1, SIX2, SIX3, and SIX4 were increased in breast cancer cells as compared to low expression in non-cancerous cells [35]. SIX1 promotes invasion and metastasis by enabling EMT through downregulation of E-cadherin, an epithelial marker, promotes angiogenesis through regulation of VEGF, and promotes Ezrin expression, which plays a role in cell adhesion [35, 36]. SIX2 upregulates ZEB2 to downregulate E-cadherin, both of which are related to EMT and MET [35]. SIX1 knockout in animal models has decreased tumor size [36].

The runt-related transcription factor (RUNX) family of transcription factors has three members, each with different physiological and developmental roles [37]. RUNX1 and RUNX3 act as tumor suppressors in breast cancer cells, while RUNX2 can act as either a tumor suppressor or an oncogene in cancer cells [37]. Expression levels of RUNX2 are increased in breast cancer tumors [38]. RUNX2 is involved in responding to DNA damage, regulating VEGF, and in several estrogen signaling pathways and the TGFβ pathway [38]. RUNX2 is important to osteogenesis and bone formation, so it is linked to breast cancer metastasis in the bone as it allows cancer cells to execute osteomimicry and invade bone composition [38].

The myelocytomatosis (MYC) oncogene family consists of three members, C-MYC, L-MYC, and N-MYC, all of which belong to the superfamily of bHLH leucine zipper (bHLHLZ) DNA binding proteins [39]. MYC proteins regulate a wide range of genes involved in several cellular processes, including cell growth, differentiation, apoptosis, angiogenesis, DNA repair, protein translation, immune response, and stem cell formation [39]. These regulatory functions suggest that MYC can contribute to cancer by enhancing cell proliferation, inhibiting cell death, modulating metabolism, promoting angiogenesis, and regulating stem cell formation [39]. Amplification of c-Myc and the activation of pathways downstream are related to high metastatic ability in breast tumors [40]. Myc-amplification-mediated glutamine-related metabolic pathways are upregulated in the luminal B, HER2-positive, and TN breast cancers [40].

Kruppel-like factors (KLFs), a subgroup of the Sp1/KLF family, contains seventeen members, each with three C2H2-type zinc fingers [41]. KLFs play roles in cell proliferation, apoptosis, EMT, and invasion and are connected to pathways involving E2F, MYC, and p53 [41]. Most KLFs are ubiquitously expressed, while others have cell- or tissue-specific expression [41]. KLFs regulate metastatic processes both positively and negatively. KLF8 promotes but KLF6 and KLF9 inhibit changes in the extracellular matrix, KLF8 stimulates and KLF8 and KLF 9 downregulate invasion, KLF4, KLF 5, and KLF17 restrain and KLF8, KLF6-splice variant (SV), and KLF16 promote EMT [41–43]. KLF11 in tumor cells promotes tumor growth [44]. KLF9 represses breast cancer invasion and metastasis by upregulating E-cadherin [42]. KLF16 deletion was found to suppress EMT, migration, and invasion in breast cancer [43].

c-Jun is a protein encoded by the proto-oncogene JUN [45]. c-Jun is involved in several processes in breast cancer including proliferation, differentiation, growth, apoptosis, cell migration, and transformation [45]. c-Jun directly binds to and activates at least four genes associated with breast cancer metastasis to the lungs [45]. c-Jun is closely associated with metastasis and acts as both suppressor and oncogene in different situations [46]. c-Jun is also related to glucose metabolism, which may be a mechanism for metastasis based on how c-Jun is related to the expression of glucose transporter protein type 1 (GLUT1), a membranous glucose transporter [46]. c-Jun promotes cell growth in breast cancer by interacting with estrogen receptors [47].

Survival of primary tumor cells is crucial to metastasis, especially in the colonization step, as only the cancer cells able to survive in hypoxic conditions, against the human immune system, or against different therapies can go on to form metastases.

E2Fs contribute to tumor cell survival by also promoting cell proliferation by regulating the cell cycle. EMT transcription factors are associated with increased tumor survival and metastatic success because the EMT process often yields cancer stem cells with resistance to chemotherapy, possibly because these cells have a slower cell cycle than the rapidly dividing cells many therapies target [48]. HIFs play a large role in metastasis by providing blood to secondary tumors that would otherwise go through necrosis in deficient blood supply [49].

Angiogenesis is the development of blood vessels, a process integral to the growth and metastatic capacity of malignant tumors. By increasing angiogenesis, tumors are recruiting their own blood supply to get more oxygen and nutrients to their cells. Vascularization uses angiogenesis to supply oxygen to new areas through blood. HIFs are major transcription factors related to these processes in the cellular response to hypoxia. Activation of the HIF pathway often occurs in breast cancer to stimulate the growth of blood vessels. The concentration of microvessels in a breast cancer sample proves to be an accurate indicator of metastasis or relapse [49].

Angiogenesis in breast cancer tumors results in new vasculature that is disorganized and incomplete compared to angiogenesis in normal tissues [7]. This causes decreased drug delivery and hinders antitumor immune responses, contributing to drug resistance [7].

In terms of metastatic cancer, intravasation and extravasation describe the movement of cancer cells into and out of blood vessels, respectively. These processes are integral to how cancer cells travel through the circulatory or lymphatic system to reach distant tissues. Expression of Zeb1 and Snail1 was found to promote intravasation and transmigration [16].

Invasion refers to the penetration of neighboring tissues by cancer cells. EMT is one way that cancer cells leave the primary tumor to distant metastatic sites in the body. The transition to mesenchymal phenotype gives tumor cells stem-cell-like qualities. During EMT, the extracellular matrix is degraded to allow for invasion, when cancer cells first leave the primary tumor and enter a neighboring tissue [16]. There are three types of EMT representing different processes, and the regulation of all of them is similar [50]. The main pathways regulating EMT are the Notch, Wnt, Hedgehog (Hh), and TGFβ pathways [51]. One crucial EMT process is the loss of E-cadherin, a protein that maintains cell-cell contacts, which is downregulated by transcription factors like Snail, Slug, Ras homolog gene family, member B (RhoB), and TWIST1 [41].

Snail, Zeb, and Twist family transcription factors promote EMT pathways, making them potential therapeutic targets. Six1 and RunX2 also drive EMT [52]. HIFs transactivate Snail transcription factors and directly regulate Twist and Zeb [53]. HIF-1α-induced EMT can be eliminated through inhibiting ZEB1 [53].

Another effect of EMT is the increased resistance to chemotherapy acquired by breast cancer stem cells in the process as they have increased expression of anti-apoptotic and DNA repair genes [54].

MET, the reverse process of EMT, is important to the colonization step of metastasis to establish secondary tumors [16]. MET at metastatic sites is induced by the re-expression of E-cadherin, giving these secondary tumor cells greater susceptibility to chemotherapy [55].

The most successful cancer treatment strategy targeting transcription factors so far has been through nuclear hormone receptor ligand binding domains, in other words, molecules that bind to specific receptors [52]. Drugs currently used to treat breast cancer affect the estrogen receptor, androgen receptor, retinoic acid receptor, and glucocorticoid receptor [52]. The estrogen receptor is a particularly effective target as approximately 75% of breast cancers express it [52]. Widely used current breast cancer therapies include tamoxifen, a selective estrogen receptor modulator, and combination chemotherapy with trastuzumab to target HER2 and bevacizumab to target VEGF [12].

Targeting protein-protein interactions between transcription factors, co-activators, and co-repressors impacts gene expression [52]. The interaction between RUNX1 and ETS1, for example, occurs for DNA binding [52]. This strategy involves using inhibitors to block the proteins. These inhibitors can be small compounds, peptidomimetics, or stapled helix peptides [32].

Transcription factors are naturally regulated in cells through ubiquitylation and proteasomal degradation [52]. E3 ubiquitin ligases drive these processes [52]. One successful example is an inhibitor of the E3 ubiquitin ligase called von-Hippel Lindau (VHL) which interacts with the HIF-1α transcription factor [52]. Deubiquitinases prevent degradation; for example, ubiquitin specific peptidase 10 (USP10) protects SLUG and SNAI2 from degradation, and DUB3 increases SNAI1 while protecting TWIST and SLUG [52].

Proteolysis targeting chimeras (PROTACs) can also degrade transcription factors [52]. Using PROTACs involves a ligand that binds to an E3 ligase covalently attached to a ligand that binds to a specific protein, which drives ubiquitylation and subsequent proteasome-mediated destruction [52]. PROTACs are a promising treatment method because they can knock down all functions of a transcription factor through complete degradation that may not be possible with inhibitory substances, which may also require lower dosage and improved efficacy [52].

The binding pockets of transcription factors can be targeted to prevent them from initiation transcription. Some transcription factors involve ligands, so one approach to inhibit these is to develop structural derivatives of the natural ligands for that transcription factor [32]. Most oncogenic transcription factors do not have these ligands, so a more effective approach for those would be to target the DNA-binding pocket of the protein through other protein interactions or direct binding to the DNA [32].

Biomarkers are measured substances used to evaluate normal processes or responses to a treatment that can be prognostic and predictive [7]. Transcription factors can not only be targeted directly for treatment but they can be evaluated for diagnostic and prognostic purposes as biomarkers. Measuring and comparing levels of transcription factors can allow for correlation between those levels and metastasis, patient survival, etc.