Regulation of epidermal growth factor receptors: The role of c-Cbl, Cdc42, and miRNAs in breast cancer.

1
Introduction
The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is frequently dysregulated in breast cancer, particularly in subtypes such as triple-negative breast cancer (TNBC) [1]. Upon binding to its ligands (e.g., EGF), EGFR undergoes conformational changes that induce dimerization and autophosphorylation of key tyrosine residues in its intracellular domain, which in turn recruits adaptor proteins and activates downstream oncogenic signaling pathways including RAS/MAPK, PI3K/AKT, and STATs that drive proliferation, migration, survival, and therapy resistance [1]. Dysregulated EGFR expression and signaling correlate with aggressive tumor phenotypes, therapeutic resistance, and poor clinical outcomes in breast cancer subtypes [1]. Regulation of EGFR signaling is intricately controlled, not only at the level of ligand binding and kinase activity, but also through post-translational modification and receptor turnover. Ubiquitination, mediated by E3 ubiquitin ligases such as Casitas B-lineage lymphoma (c-Cbl), is a key mechanism facilitating endocytosis and lysosomal degradation of activated receptors, thereby attenuating signaling output. c-Cbl recognizes phosphorylated EGFR at specific motifs and catalyzes ubiquitin attachment, marking the receptor for internalization and degradation [2]. The activity of c-Cbl, in particular, is subject to upstream modulation by small GTPases such as Cdc42 [3]. In breast cancer models, hyperactivation of Cdc42 has been shown to impair the interaction between c-Cbl and activated EGFR, reducing receptor ubiquitination and delaying degradation. This effect sustains surface EGFR levels and prolongs oncogenic signaling, contributing to enhanced proliferation and aggressive phenotypes [3]. Concurrently, microRNAs (miRNAs) have emerged as potent post-transcriptional regulators of EGFR and signaling network. miRNAs can directly target EGFR mRNA or modulate upstream regulators and downstream effectors, thereby influencing receptor expression and downstream signal transduction [4]. For example, differential expression of miRNAs has been implicated in the regulation of EGFR pathway components and the tumor-promoting microenvironment in breast cancer. miRNAs such as miR-7 and others have been documented to interact with EGFR signaling axes, while broader miRNA expression signatures correlate with disease progression, therapeutic responses, and clinical outcomes across breast cancer subtypes [4].
The integrated regulation of EGFR by c-Cbl, Cdc42, and miRNAs describes a multidimensional control system in breast cancer: c-Cbl mediates receptor ubiquitination and signal attenuation; Cdc42 regulates the accessibility and activity of the ubiquitin machinery; and miRNAs are involved in the fine-tuning of both receptor and signaling components at the transcript level. Disruption at any of these nodes can lead to persistent EGFR signaling, enhanced oncogenic phenotypes, and resistance to targeted therapies. Delineating these mechanistic layers does not only deepens our understanding of EGFR biology in breast cancer but also reveals convergent vulnerabilities that may be exploited for precision therapeutic interventions.

2
Breast cancer
Breast cancer affects humans, particularly females, globally, and stands as the prevailing malignant tumor. In 2022, there were about 670,000 fatalities and over 2.3 million new cases reported globally [5,6], constituting up to 36% of all oncology cases [7,8]. The prevalence of breast cancer is escalating globally, particularly in industrialized nations, where nearly half of all cases are found [8,9]. Sub-Saharan Africa seems to have a lower incidence of illness than high-income nations, although the mortality rate is much higher there. [10]. The observed phenomenon is attributed to the dearth of information leading to inadequate data that marginally represents the true disease burden within the sub-region [[10], [11], [12]].
Ghana has an incidence of 18.4% for female breast cancer [5,13], and it is estimated that about 2900 new cases are diagnosed annually [14,15]. The disease exhibits significant heterogeneity [5], which is observed due to variations in genomic and epigenomic, as well as transcriptomic and proteomic traits of the cancer cells [16]. The variations in traits influence various tumor features, including growth rate, cell death, metastasis, and how the cancer responds to treatment [17].
Variable and non-variable risk factors exist for breast cancer [16,18]. Level of physical activity, radiation therapy history, exposure to diethylstilbestrol, use of hormonal replacement therapy, obesity status, alcohol consumption, smoking, exposure to chemicals, excessive exposure to artificial light, consumption of processed foods, and inadequate vitamin supplementation are among the variable factors [16,17,19] whilst genetic mutations, history of breast or ovarian cancer in family, gender, age, race and ethnicity, non-cancerous breast disorders, menstrual and menopause patterns, breast tissue density, breast cancer history, and breastfeeding are among the non-variable factors [16,18].
Five subtypes of breast cancer have been identified by molecular characteristics [20]: Luminal A, which is hormone receptor-positive but negative for human epidermal growth factor receptor 2 (HER2); Luminal B, positive for both hormone receptors and HER2; HER2-enriched, which is negative for hormone receptors but positive for HER 2 receptors; basal-like, also known as triple negative, which lacks hormone receptors and HER2; and normal breast-like cancer which is often classified as hormone receptor negative, and HER2-negative (similar to TNBC) but expresses genes that are associated with normal mammary epithelial cells rather than tumor cells [21,22]. According to a study that looked into the variation of breast cancer molecular subtypes in Africa, there are significant regional differences, with 56.3% of instances being luminal, 12.6% being HER2-positive, and 28.1% being triple-negative [23]. West Africa has the highest rate of triple-negative breast cancer (45.7%), whereas Central Africa has the lowest rate (14.9%) [24]. In one study, 82% of Ghanaians were diagnosed with triple-negative breast cancer (TNBC) [13], compared to 26% of African Americans and 16% of white Americans in another study [12]. This indicates that Ghanaians had a threefold greater rate of TNBC compared to both African and white Americans [25]. Newman et al., reports that West African ancestry was substantially associated with both the existence of germline mutations linked to breast cancer risk and the prevalence of triple-negative breast cancer (TNBC), which was highest in a Ghanaian group. Additionally, they revealed a link between the Duffy-null allele and a higher incidence of TNBC [26]. The observed high prevalence of TNBC among Ghanaian women suggests that genetic factors associated with West African ancestry may contribute significantly to disease susceptibility. These findings underscore the need for further genomic studies to identify population-specific risk alleles and elucidate the hereditary mechanisms driving TNBC in the Ghanaian population.

3
Epidermal growth factor receptor (EGFR)
The epidermal growth factor receptor (EGFR) is part of a family of transmembrane receptors known as the human epidermal growth factor receptors (HER/ERBB). The family is made up of EGFR also known as HER1or ERBB1, HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4) [5]. HERs are receptor tyrosine kinases (RTKs) which serve as conduits for extracellular signals into the cell and exert influence on nuclear activity through tyrosine signaling [25]. Fig. 1 depicts the receptor, which consists of a transmembrane domain, an intracellular catalytic tyrosine kinase domain, a glycosylated extracellular ligand-binding domain, and a regulatory domain.
The regulation of cellular processes such as migration, differentiation, proliferation, and survival depends on these receptors [27]. EGFR is a single polypeptide chain of 1186 amino acids and weighs 170KD [27]. The extracellular region's 620 amino acid structure is made up of two domain units: a ∼190-amino acid L domain that appears twice in tandem as domains I and III, and a ∼120-amino acid cysteine-rich domain that is repeated as domains II and IV [28]. According to studies, ligands interact with domains I and III, and the formation of an inter-receptor dimer is encouraged by an extended finger-like protrusion from domain II [28,29].
EGFR, like the other HER family, exist as individual monomers in their inactive state, but upon binding with ligands the receptor undergoes conformational changes leading to the formation of dimers [30]. Dimerization can occur either as homodimers or heterodimers [30] with HER2 functioning as the favored dimerization partner [29]. The dimerization process is crucial for the activation of HER receptors because it causes tyrosine residues in the intracellular domain to become phosphorylated, which in turn activates signaling routes that affect cellular functions. [31]. Different types of ligands interact with the HER receptors; neuregulins (NRGs), a family of peptides with a variety of forms, comprises of most of the ligands that interact with HER3 and HER4. All neuregulins-mediated signaling is channeled through the mitogen-activated protein kinase (MAPK) pathway [30,32]. There are no identified ligands capable of promoting the formation of HER2 homodimer, indicating that no known ligand directly binds to HER2 [30]. Seven distinct ligands activate EGFR: heparin-binding EGF-like growth factor, betacellulin, epigen, transforming growth factor alpha (TGF-α), amphiregulin, epidermal growth factor (EGF), and epiregulin [31]. However, the primary cause of EGFR activation in cancer has been identified as genomic locus amplification and point mutations, as well as the involvement of transcriptional upregulation and excessive ligand production through autocrine/paracrine mechanisms [33]. When a ligand attaches to EGFR, it causes homodimerization or heterodimerization and transphosphorylation, activating downstream molecules such as Ras, Janus-activated kinase (JAK), phosphatidylinositol 3-kinase (PI3K), and phospholipase Cγ (PLCγ) [31]. Fig. 2 displays a schematic of the EGFR signaling pathway following dimerization.
Elevated EGFR and its ligand levels are a common characteristic of many cancer types and might contribute to solid tumor development. Overexpression of EGFR has been found in 10 different cancer forms [34]: EGFR is a strong prognostic marker in esophageal, cervical, ovarian, bladder, and head and neck cancers, with increased expression leading to lower survival rates [34]. EGFR was also associated with lower survival rates and provided only moderate predictive information for colorectal, breast, endometrial, and gastric cancers [33,34].
3.1
EGFR regulation by CBL proteins
Casitas B-lineage lymphoma (Cbl) proteins, a collection of proteins that function as vital ubiquitin ligases and are necessary for controlling tyrosine kinase signaling pathways, is at the center of EGFR regulation [35]. Cbl proteins belong to the RING finger (RF) family and negatively regulate a range of receptor tyrosine kinases (RTKs), including EGFR [36]. There are three mammalian Cbl proteins: c-Cbl, Cbl-b, and Cbl-c as illustrated in Fig. 3.
The N-terminal region of all Cbl proteins is well-conserved and comprises two domains that are critical to their function. The first, tyrosine kinase binding (TKB) domain, is required for tyrosine kinases to identify and attach to phosphorylated tyrosine residues [36,37]. The ring-finger domain follows and catalyzes the E3 ubiquitin ligase activity that Cbl proteins is noted for [36,37]. Conversely, the proteins' C-terminal regions differ; Cbl-c possesses a rather short C-terminal domain, whereas the C-terminal of Cbl-b and c-Cbl is vast and rich in proline [38]. Additionally, c-Cbl and Cbl-b have UBA domains that allow Cbl to homodimerize, whereas Cbl-c does not [36]. The three-step enzymatic pathway that Cbl proteins employ to control receptor tyrosine kinases is made up of the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3) [16,39]. In order to facilitate ubiquitin transfer onto E2, E1 first activates ubiquitin in an ATP-dependent step, starting the ubiquitination process. Following that, the active ubiquitin is moved from E2 to E3 [16], where target proteins (e.g., EGFR) undergo either mono or polyubiquitination. Chains consisting of four or more ubiquitins (polyubiquitination), commonly observed on cytoplasmic proteins, are effectively recognized by the proteasome, triggering the degradation of the target protein (Rao et al., 2002; Sadowski and Sarcevic, 2010). Non proteolytic processes like endocytosis, histone modulation, DNA repair, viral budding, and nuclear export are, however, signaled by mono-ubiquitination [37,40].
Ubiquitination functions as a molecular switch in EGFR by directing receptors towards degradation and thereby reducing the strength of the signaling pathway [41]. Tyrosine phosphorylation and intracytoplasmic tail ubiquitination are among the structural and biochemical changes that EGFR experiences after being activated by the ligand EGF [42]. Either clathrin-mediated endocytosis (CME) or non-clathrin-mediated endocytosis (NCE) can internalize active EGFRs in the cell [41]. NCE becomes necessary for EGFR degradation at high EGF concentrations more than or equal to 10 ng/mL, protecting cells from excessive signaling, whereas CME is prevalent at small EGF concentrations less than or equal to 2 ng/mL and is needed for maintaining EGFR signaling [41,43].
Recent studies have highlighted the non-redundant roles that three mammalian Cbl proteins play in EGFR regulation and breast cancer biology. c-Cbl, the prototypical E3 ligase for EGFR, is responsible for EGFR polyubiquitination which causes EGFR degradation by proteasome [44,45], and its dysregulation has been implicated in aberrant EGFR signaling and tumor progression [46,47]. Cbl-b, although structurally similar to c-Cbl, displays unique binding preferences and temporal activity, with Pennock and Wang 2008 demonstrating that whereas c-Cbl acts at early stages of EGFR trafficking, Cbl-b associates later and produces a second wave of ubiquitination that is essential for receptor degradation [48,49]. A more recent report confirmed that c-Cbl and Cbl-b operate independently through distinct receptor interaction modes, with c-Cbl relying mainly on Grb2-mediated binding and Cbl-b preferentially engaging pY1045, which jointly but non-redundantly control EGFR ubiquitination, trafficking, and signaling [50]. In breast cancer, high Cbl-b expression correlates with suppressed tumor spread and favorable prognosis, underscoring its role in immune modulation rather than direct EGFR turnover [51,52]. Cbl-c lacks UBA domain and has a truncated C-terminal region and shows limited capacity for receptor regulation and is considered a weaker or context-dependent contributor [36,38]. The findings suggested that while the Cbl proteins can compensate for each other under certain conditions, their hierarchical functions are subtype-specific; c-Cbl dominates receptor downregulation in EGFR-driven tumors, Cbl-b modulates immune and signaling pathways with prognostic impact, and Cbl-c plays a minor or supportive role.
Breast cancer subtypes exhibit distinct molecular drivers and c-Cbl network behaviors that underpin their clinical heterogeneity. Luminal A and B tumors generally maintain higher c-Cbl expression, enabling efficient ubiquitination and degradation of EGFR, which affects downstream MAPK/AKT signaling and results in slower growth and responsiveness to endocrine therapy [53]. In HER2-enriched cancers, HER2 amplification often bypasses c-Cbl regulation and contributes to tamoxifen resistance, though c-Cbl restoration can reverse this phenotype [54]. TNBC, however, shows markedly reduced or dysfunctional c-Cbl, leading to impaired EGFR ubiquitination, receptor recycling, and prolonged signaling cascades that drive aggressive phenotypes, therapeutic resistance, and poor prognosis [55]. Basal-like TNBC demonstrates strong reliance on EGFR and integrin/Src crosstalk, and further magnifying the impact of c-Cbl deficiency [55,56].

3.2
EGFR regulation by Cdc42
Cdc42 belongs to the Rho family of GTPases which is a subclass of small GTP-binding proteins in the Ras superfamily and normally have a molecular weight between 20 and 25 KDa. Rho-GTPases are present across various eukaryotic organisms, spanning from plants to humans [57] and function as a switch; they respond to various stimuli by converting between an activated GTP-bound state and a deactivated GDP-bound state [58,59]. The stimuli include soluble factors like growth factors and cytokines, in addition to communications with neighboring cells or extracellular matrix via integrins [58,60].
Cdc42 is a 21 KDa molecular weight protein with a sequence of 191 amino acids [57]. The protein exists in two distinct isoforms: Cdc42a, also known as Cdc42p or Cdc42Hs, and Cdc42b, also known as brain-derived Cdc42p or G25K GTP-binding protein [61]. All human tissues express Cdc42a, while the brain is the only organ where Cdc42b is expressed [57]. Cdc42 is influenced by GTPase-activating proteins (GAPs), guanine nucleotide-exchange factors (GEFs), and guanine nucleotide dissociation inhibitors (GDIs) [46]. By increasing GTPase activity, GAPs deactivate Cdc42; GEFs promote the active GTP-bound Cdc42 by facilitating the exchange of GDP for GTP; and GDIs sequester Cdc42 in the inactive GDP-bound form [46].
Cdc42 largely regulates EGFR signaling in breast cancer by influencing proliferation of the cancer cells. Specifically, upregulation of Cdc42 impairs c-Cbl activity and modulates the interactions between c-Cbl and EGFR, resulting in the inhibition of ubiquitination, therefore the inability of the proteosome to degrade EGFR [62,63].

4
MicroRNAs as regulators of gene expression in breast cancer
MicroRNAs (miRNAs) are small non-coding RNA molecules that bind to target mRNA molecules to modify gene expression at the post-transcriptional level. Initially discovered in Caenorhabditis elegans, microRNAs are found in most eukaryotes, including humans [64]. Over the years, extensive research has consistently underscored the significance of miRNAs in regulating signaling pathway-driven processes such as cell division, apoptosis, development, differentiation, and metabolism [65,66]. Oncogenic miRNAs (oncomiRs) are microRNAs that promote cell division but prevent apoptosis. They are overexpressed in malignant cells. However, microRNAs that inhibit cell division and encourage apoptosis function as tumor suppressor miRNAs (tsmiRs), as a result, they are downregulated in cancer cells. [67,68]. For example, mir-17 cluster of miRNAs are implicated in and MiR-21, another miRNA displaying an evident anti-apoptotic function, is overexpressed in glioblastoma tumor tissues and cell lines [67,69].
Current studies highlight diverse roles of miRNAs in shaping tumor biology, influencing clinical outcomes, and opening new avenues for therapeutic intervention. Collectively, these findings underscore the importance of miRNAs as both mechanistic drivers and translational biomarkers in breast cancer research [70]. For example, Dastmalchi et al., showed that miR-424-5p activated PTEN, which inhibited the PI3K/AKT/mTOR pathway, an essential regulator of cell growth and survival. This, in turn, reduced cell proliferation in MDA-MB-231 breast cancer cells [71]. Fontana et al., 2025 developed a miRNA-based prognostic model using patient data to accurately predict distant metastasis in breast cancer. This work emphasizes the utility of miRNA expression profiles as robust clinical biomarkers for outcome prediction and risk stratification across diverse breast cancer subtypes [72]. Profiling of miRNAs in invasive ductal carcinoma revealed extensive differential miRNA expressions, with distinct signatures that stratify tumors according to molecular subtype, histological grade, and disease stage. Network analyses have demonstrated that miRNA alterations converge on critical signaling pathways, including epithelial-to-mesenchymal transition and cellular plasticity, which are fundamental drivers of tumor progression [73]. Sun et al., 2025 also demonstrated that miR-518c-5p and miR-4524a-3p promote immune escape and chemoresistance in triple-negative breast cancer, indicating how miRNA dysregulation shapes tumor–immune interactions and treatment response in an aggressive subtype which lacks targeted therapies [74]. In the context of metastatic progression, miR-24-2-5p has been shown to regulate the early stages of breast cancer bone metastasis, and highlights the critical role of miRNAs in organ-specific metastatic colonization and in modulating tumor–stromal interactions [75].
Certain miRNAs bind to the 3′ UTR of EGFR mRNA, resulting in the suppression of EGFR expression and downstream signaling. miR-218, for example, has been experimentally validated to target EGFR mRNA, reducing both EGFR protein and mRNA levels [76]. In TNBC models, overexpression of miR-218 decreased proliferation, invasiveness, and resistance by repressing EGFR expression through RISC-mediated mRNA decay and translational inhibition [76]. Other miRNAs indirectly influence EGFR activity by targeting proteins that regulate EGFR expression or stability. BRCA1 binds MIR146A promoter resulting in an increase in miR-146a transcription and thereby attenuating EGFR levels, and loss of miR-146a have been shown to correlate with higher EGFR and poorer outcomes in basal-like/TNBC [77]. miR-218-5p on the other hand increases EGFR levels by repressing LRIG1, a negative regulator of EGFR family signaling and thereby enhancing tumor aggressiveness [78]. Conversely, EGFR signaling has also been reported to suppress miRNA maturation, creating a feedback loop that favors tumor progression [79]. Under stress conditions such as hypoxia, activated EGFR phosphorylates AGO2 and prevent Dicer binding and lead to the suppression of maturation of specific miRNAs. The suppression establishes a feedback loop in which EGFR signaling downregulates tumor-suppressive miRNAs, promoting cancer cell survival, invasiveness, and overall tumor progression [79].
4.1
Translational challenges and emerging delivery platforms for miRNA-Based therapeutics in breast cancer
Early-phase and first-in-human research using miRNA regulation or delivery platforms in other solid tumors offer significant translational insights, even though no miRNA-based treatment has yet reached phase III clinical trials in breast cancer. MiRNA-loaded delivery vehicles, for example, have been tested in mesothelioma, showing that systemic miRNA administration in patients is feasible and build technological and clinical frameworks that could be modified for miRNA-based therapy approaches in breast cancer [80]. MRX34 clinical trial (NCT01829971) was a first-in-human Phase I study that evaluated a liposomal miR-34a mimic in patients with advanced solid tumors [81]. Although on-target gene modulation and modest antitumor activity were observed, particularly in hepatocellular carcinoma and melanoma, the trial was terminated prematurely due to severe immune-mediated toxicities, including fatal adverse events. Albeit it provided proof-of-concept that systemic miRNA delivery can modulate target gene networks in human subjects and showed some target engagement and clinical activity [81]. Emerging delivery platforms and combination strategies are advancing the potential for miRNA-based therapies in breast cancer. RNA nanoparticles functionalized with EGFR- or stem-cell marker–specific aptamers have demonstrated selective delivery of anti-miR-21 to TNBC cells in preclinical models, achieving targeted uptake and inhibition of oncogenic pathways [82]. Similarly, immunoliposomal systems co-delivering miRNA inhibitors, such as anti-miR-155, alongside chemotherapeutic agents have shown tumor-specific delivery and synergistic antitumor effects in HER2-positive breast cancer models [83]. These approaches highlight the feasibility of precise, combinatorial miRNA therapies and provide a foundation for potential translation into clinical trials. Beyond conventional lipid nanoparticles, engineered gold nanoparticles and mesoporous silica nanoparticles have been developed to stabilize and deliver miRNA mimics, such as miR-206 and miR-200c-3p, offering next-generation delivery platforms with enhanced specificity and reduced toxicity for potential clinical applications [84].
Despite preclinical evidence supporting the therapeutic potential of miRNAs in breast cancer and other malignancies, successful translation into clinical practice remains limited. This limitation stems from several interrelated challenges ranging from off-target toxicity to delivery inefficiencies and biological heterogeneity which hinder clinical progress. A major challenge in miRNA-based therapeutics is due to partial complementarity of miRNA–mRNA interactions, which enables a single miRNA to regulate numerous transcripts. While the partial complementarity confers broad regulatory potential, it also increases the risk of off-target gene modulation by synthetic miRNA mimics or inhibitors and potentially resulting in unintended pathway perturbation and systemic toxicity in non-target tissues [85]. These off-target interactions complicate safety profiles and have been a central factor in clinical setbacks such as the MRX34 trial termination due to immune toxicity [81].
Efficient and safe delivery remains a central challenge in miRNA therapeutics. Naked miRNAs in circulation are rapidly degraded and cleared, and therefore there is the need for chemical modification or carrier-based systems to improve miRNAs stability and tumor exposure [80]. Tumor-specific delivery is further hindered by poor vascularization, high interstitial pressure, and dense extracellular matrices that limit nanoparticle penetration and uniform distribution [85]. In addition, many delivery platforms preferentially accumulate in off-target organs, particularly the liver and spleen, raising risks of toxicity and immune activation [85]. Regulatory evaluation of miRNA therapies as complex biologic-device products also demands rigorous assessment of manufacturing consistency, immunogenicity, pharmacokinetics, and biodistribution, which substantially prolong development timelines and increase translational costs [83].
Beyond technical barriers, the intrinsic biological complexity of cancer poses a major challenge for miRNA-based therapies. Tumor heterogeneity, encompassing diverse cancer cell states as well as stromal and immune components, leads to context-dependent miRNA expression and function, and limiting the impact of modulating a single miRNA. Interpatient variability in miRNA profiles, tumor microenvironments, and immune status further influences therapeutic efficacy and toxicity [86]. Together, these interpatient variability factors highlight the need for biomarker-driven patient stratification and rational combination strategies integrating miRNA therapeutics with targeted or immunotherapeutic approaches [86]. These challenges are suggestive of miRNA therapeutics requiring a tailored development approach; progress in precision delivery platforms, enhanced prediction of off-target effects, and comprehensive mapping of miRNA regulatory networks will be critical in translating preclinical promise into clinical success. Systematic resolution of the identified barriers may ultimately allow miRNA-based therapies to serve as effective modulators of oncogenic signaling in breast cancer and other malignancies.

5
Conclusion
The regulation of HER and associated signaling pathways presents a complex outlook on the understanding of breast cancer. Important signaling pathways that underpin the regulation of HER, particularly EGFR, have been uncovered by this review, which has also elucidated the roles of signaling molecules such as Cdc42 and regulatory miRNAs in breast cancer development. Despite substantial advancement, there are still several unresolved concerns about the molecular intricacies of breast cancer.
Although EGFR's involvement in the pathophysiology of breast cancer is well recognized, further research is still required to fully comprehend the molecular processes underlying receptor dimerization and downstream signaling effects that result in different breast cancer subtypes. The precise mechanisms by which Cdc42 influences EGFR signaling and its impact on breast cancer progression could provide valuable insights into potential therapeutic targets and therefore need to be investigated. Functional characterization of breast cancer–specific miRNAs is needed to distinguish between oncogenic and tumor-suppressive miRNAs in different breast cancer subtypes. This will aid in understanding the complex regulatory network of miRNAs and downstream effectors and guide discovery into new biomarkers and therapeutic targets. Developing miRNA mimics (for tsmiRs) or inhibitors (for oncomiRs) tailored to breast cancer is a promising area. Future research could focus on delivery strategies (e.g., nanoparticles, exosomes) and minimizing off-target effects.

Consent for publication
All authors have given permission to submit the paper for publication.

Ethics approval statement
This is a review paper, and no human or animal data was used. Ethical approval is therefore not needed for the study.

Funding statement
No funding was obtained for this study.

CRediT authorship contribution statement
Sabina Ekua Andam: Conceptualization, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Emmanuel Ayitey Tagoe: Conceptualization, Formal analysis, Project administration, Supervision, Writing – review & editing. Anastasia Rosebud Aikins: Conceptualization, Formal analysis, Project administration, Supervision, Writing – review & editing. Osbourne Quaye: Conceptualization, Formal analysis, Investigation, Project administration, Supervision, Writing – original draft, Writing – review & editing.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.