The Role of Oral Fusobacterium nucleatum in Female Breast Cancer: A Systematic Review and Meta-Analysis

Introduction Breast cancer is the world's most prevalent malignancy, with an increasing incidence and a predisposition for postpubertal females from all cultural and ethnic backgrounds. More recently, oral Fusobacterium nucleatum species have been observed in cancerous human breast tissue, drawing attention to the role of microbes in cancer pathogenesis. Objectives Investigating oral Fusobacterium nucleatum species as potential biomarkers for female-specific breast cancer. Methods A systematic search in The Central Register of Controlled Trials, EMBASE, EBSCO, NCBI, and MEDLINE databases was undertaken from the 1st January, 1983–31st March, 2022. Articles included were in English and based on women between the ages of 18–96 years with confirmed gingivitis/periodontal disease and breast cancer diagnoses from registered specialists. Authors extracted data independently, and a meta-analysis of risk estimations measuring associations between oral Fusobacterium nucleatum species and female-specific breast cancer was elucidated via calculated relative risks and 95% confidence intervals. Results AXIS tool analysis revealed 78.70% of articles with a positive correlation between oral Fusobacterium nucleatum and female-specific breast cancer. The risk of breast cancer development increased with significant levels of oral Fusobacterium nucleatum due to gingivitis/periodontitis (relative risk = 1.78, 95% confidence interval = 1.63–1.91). Low-moderate statistical heterogeneity was found (I2 = 41.39%; P = 0.02), and the importance of periodontal status on breast cancer pathogenesis was determined (relative risk = 1.24, 95% confidence interval = 1.01–1.30). Conclusions Oral Fusobacterium nucleatum species are a risk factor for breast cancer development, thus elevating their biomarker potentiality.


Introduction
Breast cancer (BC) is the world's most prevalent malignancy, with a predisposition for postpubertal females [1]. In 2020, 2. 261, 419 million women were diagnosed with BC, resulting in 684,996 deaths worldwide [2]. Estimations suggest that 1 in 8 women will be diagnosed with pernicious BCs during their lifetime [3]. Numerous treatments are available, such as radio-and chemotherapies, anticancer medicaments, hormone therapy, and strategically targeted biological therapies. Over the past decade, mortality rates have signifcantly diminished, with elevations in BC survival rates [1].
Despite all international eforts to raise public awareness, outreach programmes, frequent testing for the condition in women above 40 years, and extensive research into the various cell-signalling pathways responsible for BC development, its incidence is rising amongst postpubertal females of all cultural and ethnic backgrounds [1][2][3].
Attention has been drawn to the signifcance of microbes and their role in cancer pathology initiation/activation, with further support for an association between disruptive microbial homeostasis and BC [4][5][6][7][8]. Te oral cavity is a cornucopia of microorganisms, with approximately 700 identifable bacterial species that collectively encompass the oral microbiome [4]. Its environment contains particular oral habitats, such as the hard, nonshedding external surface of human dentition, the gingiva, and the dorsum of the tongue. Tese appreciable loci permit unique microbial niche formations creating long-short distance microbial interactions [4].
When the intraoral environment becomes overburdened with dental plaque accumulations, this can cause immediate microbial dysbiosis, initiating acute infammatory responses that result in gingivitis [9]. Accumulation of dental plaque over prolonged periods instigates chronic infammatory responses, causing periodontitis [9]. Periodontitis is a rife disease associated with both microbial dysbiosis and infammatory responses, afecting approximately 45-50% of adults >30 years old and >60% of people aged >60 years old [10]. It is characterised by loss of connective tissue attachment, gingival infammation, alveolar bone resorption, and loss of dentition [10]. Disparate from other infectious diseases, periodontitis is caused by bacteria from within the oral cavity and accelerated by an increase in microbial biomass as opposed to compositional alterations within a specifc bacterial community. Tis premise concurs with an apparent increase in bacterial load (and so periodontal disease) in murine models and in humans as they grow older [11]. During the progression of infammation in PD, a multifunctional molecule (endothelin (ET)-1) is overexpressed within the human body, secreted by endothelial cells after exposure to pathogenic bacteria, and is a dominant vascular infammatory mediator [10,12]. Reports have stipulated that serum proinfammatory cytokines such as IL-1, IL-6, and IL-8 are responsible for the upregulation of ET-113 [10,13]. Furthermore, the conjecture that a combination of chronic infammatory markers associated with systemic diseases, certain oral bacteria and their by-products leaving the oral cavity and infltrating the systemic circulatory system, aids cancer progression to distant bodily sites [14] Fusobacterium nucleatum (FN) is one such important virulent pathogen. It is a spindle-shaped, nonspore-forming anaerobe, identifed as one of the most common gramnegative oral microbial species [15,16], with a signifcant contribution to bioflm development and maturation accompanying dysbiotic alterations in dental plaque [9]. More recently, FN has been observed in cancerous human breast tissue, with stimulation of BC advancement in murine models. [17,18], and a plethora of articles have been published over the past decade evidencing a link between the microbiome and cancer [19][20][21]. In 2020, a study of breast ductal carcinoma cells in situ (BDCIS) were exposed to have signifcantly elevated immunoreactivity for ET-1 when compared to healthy breast tissue. Furthermore, signifcant levels of immunoreactivity were demonstrable in invasive tumours when contrasted with BDCIS [22].
Te results highlight the actively prominent role played by oral FN species and endothelin molecules in the creation of a perfect proinfammatory microenvironment evident in individuals diagnosed with PD and its link to accelerating BC pathogenesis [23][24][25].
Over time, innovative periodontal surgical techniques have come into play with the purpose of slowing/arresting PD progression and regenerating lost periodontal tissues. Several fap surgical designs have been proposed with modifcations to minimise periodontal surgical trauma (PST); however, the traditional method to access fap surgery (2 fap refections of buccal and lingual/palatal) remains the advocated surgical procedure for pocket reduction/elimination [26]. Tis is where minimally invasive surgery (MIS) has been introduced to appease such issues [27].
MIS is a novel approach that aims to respect hard and soft tissues via minimal fap refections, thus reducing postoperative pain, encouraging healing, and improving clinical outcomes [28]. Since 2007, the single fap approach (SFA) has been modifed and evolved to better suit a more minimally invasive surgical technique (MIST) for PD osseous defects, with the purpose in minimising surgical trauma. A 2013 study reported minimal bone loss when utilising MIST compared with conventional surgeries [29]. SFA permits fap repositioning and attachment to the undetached papilla, thereby inhibiting contamination by blood clots and reducing post-operative recession [30]. Tis reduces the risk of stimulating PD bacteria by upregulating proinfammatory cytokines and endothelins, which enter the systemic circulatory system and travel to distant anatomical sites, potentially instigating BC pathogenesis. Moreover, performing MIST using dental loupes increases precision, enhances rapid wound healing, and reduces postoperative pain [30].
Te signifcance and functionality of the human microbiome are mainly derived from a plethora of studies into the human gut, the origin of approximately 99% of the microbial mass responsible for the maintenance of homeostatic gross metabolic function [31]. Comparatively, there are far fewer articles evaluating the importance of the oral microbiome and its role in breast cancer pathogenesis. To our knowledge, no meta-analysis has been conducted specifcally on FN species, examining its potential as a biomarker for female-specifc BC. With this in mind, our aims are to: (i) highlight the evidence to date and understand the impact of oral FN species and their link in BC pathogenesis; (ii) examine the link between endothelin (ET-1) molecules and oral FN species and their roles in infammatory cytokine activation, PD, and BC pathogenesis; (iii) discuss surgical treatments for PD (specifcally periodontal fap designs) and the associated increase in risk of PD onset; (iv) appreciate the fundamental part of oral FN species in BC pathogenesis and their potentiality as BC biomarkers (v) raising awareness of the complex interactions of oral bacteria and infammatory cytokines at a cellular level as a novel approach for therapeutic targets, thus improving future PD and BC prognosis.

Protocols and Registration.
Tis systematic review was created in accordance with the preferred reporting system for systematic reviews and meta-analyses (PRISMA) [32]. Also refer to the PRISMA 2020 expanded checklist in the supplemental appendix: Description 1. FG, RCG, and RGM carried out thorough, centralised evaluations of peerreviewed publications on oral FN and BC pathogenesis.

Search
Strategy. Te P.I.C.O.S model of clinical questioning for evidence-based medicine was implemented by FG, RCG, and RGM as the defning criteria for article incorporation, utilising the P.I.C.O.S point system (Supplemental Appendix: Table 1), to create a summarisation of included articles analysing oral FN and BC pathogenesis (Supplemental Appendix: Table 2). A MeSH search string of studies involving the following key words was included: oral microbiome, Fusobacterium nucleatum, breast cancer, neoplasms, and adult women (Supplemental Appendix: Table 3).

Article Selection.
Te objective of this systematic review was to examine the importance of oral FN species and their potential role as biomarkers for female-specifc BC. Women younger than 18 years of age were excluded. Full-text articles published from January 1, 1983, up to and including 31 st March, 2022 involving human, postpubertal females were included for analysis. Refer to Table 1for a detailed description of the inclusion and exclusion criteria.

Search Protocol.
A variety of databases were thoroughly searched as recommended by COCHRANE (Te Central Register of Controlled Trials), EMBASE, EBSCO, NCBI, and MEDLINE. Te time period from which databases were searched by FG, RCG, and RGM was from February 1 st , 2022-February 25 th , 2022. Te abstracts and titles of the articles recovered in the search were appraised within the context of the study criteria, and nonrelevant articles were discarded. Full-text articles were screened with respect to the inclusion and exclusion criteria (Table 1).
In total, three separate searches were conducted and categorised into 3 phases: phase 1 was the initial search undertaken by FG, RCG, and RGM with the purpose of collating and evaluating articles linking human microbiome dysbiosis to cancer development. Phase 2, undertaken by FG and RCG, was a more "concise" search of articles focussing on a dysbiotic relationship between varying ecosystems belonging only to the human oral microbiome and cancer development. Te fnal stage, supervised by FIG (phase 3), focussed on articles investigating a link between oral FN bacterial species and their infuence on female-specifc BC pathogenesis.
In all 3 phases, abstracts and titles were independently reviewed by FG and RCG. FG collated the required data from the selected articles to be incorporated, and data extraction were cross-checked by FG, RCG, and RGM. In instances where author discrepancy was discovered in phase 1, articles were reanalysed and progressed to phase 2. If discrepancies remained, a consensus was reached by requesting involvement by the co-authors, with FG having the fnal say.

Quality Assessment Measures.
Te methodological sections of 6 out of the 10 articles were analysed by FG, RCG, and RGM utilising the AXIS Tool (Supplemental Appendix: Figure 1), which consists of a fxed set of questions intended to scrutinize data acquisition procedures as stated in the articles while considering a myriad of factors such as the adequacy in representation of participant population, inclusion of appropriate population sample sizes, consideration of nonresponding participants, and ultimately the efect of the acquired statistical data on study reliability and consequent efect on study outcomes [35]. Te results are illustrated in the supplemental appendix section: Figure 1. Te Critical Appraisal Skills Programme (CASP) Tool was utilised by FG and RCG to appraise 4 of the included articles, questioning the obtained and stated result validity of studies and to assessing the local applicability of result fndings thus enabling extrapolation to the wider population [36]. Tese results are depicted in Figure 1.

Outcome Measures and Investigated Methodologies for
Oral FN Measurements. Te primary evaluated outcome is to establish a link between oral FN species and BC pathogenesis in adult women. Articles examining BC pervasiveness and its association with oral microbiome imbalance (with reference to FN) were considered for inclusion. Our focus for this systematic review was on cancer development and not on survival/mortality rates.
To examine specifc bacterial communities, DNA microarrays create high-throughput, quantitative and systematic analysis-especially when examining oral microbiota [37]. However, other culture-independent"omic"based methodologies, such as gel-based and polymerase chain reactive (PCR) techniques, were included.

Statistical Analysis.
From the 10 articles included, 6 articles underwent AXIS Tool and meta-critical analysis [38][39][40][41][42][43] and 4 underwent CASP Tool analysis [4,18,44,45]. Calculations and estimates of the measures of association between oral FN species and female-specifc BC were calculated from the extracted data. Microsoft Excel was utilised for graphical data representation. Te results of the quality assessment of included articles were presented in tables or fgures (Figures 1, 2 and Table 2. Supplemental Appendix: Figure 1).
25 articles were eligible for inclusion (13.23%), with a fnal total of 10 studies eventually included for analysis (40.0%), consisting of 1745 subjects ( Figure 3). Articles were excluded if: (a) studies were not written in English (b) studies were irrelevant (c) study results were generated using "in vitro" methodologies (d) free-text versions of articles were unavailable (e) articles generated results based solely upon animal experimentation (f ) studies did not mention/ investigate a link between FN and BC. Females diagnosed with Vitamin C defciency and those with a "high refned-carbohydrate diet" Grade III: Severe infammation-marked redness and oedema which covers ¾ or more of the crown of the afected tooth surface. Ulceration. Tendency to spontaneously bleed [33] Studies focussing on children <18 years) were excluded (i) Transition from the established stage to the advanced stage [34] (ii) Spread of infammation from epithelium to connective tissue both apically and laterally with concomitant collagen fber destruction [34] Study designs RCTs, prospective cohort studies, retrospective case studies, retrospective cohort studies, descriptive studies, comparative studies, crossover studies, literature reviews, clinical trials, original research articles b Abstracts, editorials, directories, nonEnglish articles, retracted studies, lectures, biographies, reviews, case reports, and other studies without a comparison group, cross-sectional studies, reports from conferences or annual meetings, editorials, opinions and in vitro studies were excluded from this review Additional eligibility criteria for inclusion: Articles stating relative risks (RRs), HRs or odds ratios (ORs) and corresponding 95% CIs, or data for their calculation a Adult females with at least 10 teeth within the oral cavity, and with at least one tooth with a probing depth and intraorally determined gingival clinical attachment level of (CAL) ≥4 mm 4 International Journal of Dentistry Our results revealed that 5 studies were implemented in North America (n samples � 45,622, n patients � 1348), 3 in South America (n samples � 1056, n patients � 331), 2 Europe (n samples � 1586, n patients � 66). Te female population age range was 18-96 years, with a generalised trend of case participants being older than healthy female control participants. An extended range of articles were sourced, with a range of publication dates from 1983-2022.
Graphical illustrations generated via CASP Tool analysis of the other 4 included articles [4,18,44,45] clearly demonstrate result validity with respect to the author's manner of critical data assessment, search methodology for the inclusion of relevant data, and the proportion of relevant articles included (Figure 1(a)). Our investigation into the overall applicability of local results was positive, indicating that the authors of more than half of the included articles considered all outcomes important (Figure 1(b)).

Metacritic Analysis.
A more detailed evaluation of the data provided by the 6 included articles was implemented, and details of article study design, follow-up periods, and dental status were examined (Table 2). How article study design infuenced the fnal result outcomes, was scrutinised via stratifcation analyses as conceded by retrospective cohort study design (n � 1) [42], case-control study design (n � 1) [41], and prospective cohorts (n � 4) [38][39][40]43].
With respect to the evaluation of specifed follow-up durational data from the included articles, it was apparent that 2 studies [38,39], which stated their patient follow-up durations as being for over a period of less than 10 years, concurred to the signifcant impact that FN species within oral bioflm has on the promotion of female-specifc BC pathogenesis (RR � 1.18, 95% CI � 1.15-1.29) ( Table 2). Comparatively, 2 of the included studies [41,43], both of which stated their patient follow-up periods as being more than 10 years, implied that the infuence of FN species microbial levels within oral bioflms statistically possessed an insignifcant efect on female-specifc BC pathogenesis (RR � 1.41, 95% CI � 0.88-1.87) ( Table 2). Evaluation of all 6 included articles [38][39][40][41][42][43] revealed the importance of periodontal status (implying the negative efects of oral FN microbial dysbiosis) on BC pathogenesis (RR � 1.24, 95% CI � 1.01-1.30) ( Table 2).

Discussion
Te result of this systematic review reveals a link between oral FN species and their role in female-specifc BC pathology, thus elevating their potential to act as biomarkers in BC. However, from our subgroup calculations, it can be elucidated that numerous cofounders, such as follow-up periods and study designs, may have infuenced the overall evaluations.
Over the past decade, much research efort has been instigated with particular emphasis to the understanding of oral microbial burden impaction on an individual's overall systemic health, and numerous articles [46][47][48] have alluded to a connection between a state of chronic gingival infammation and BC development, of which oral FN species have been named as a signifcant contributor [38,39].
Te Human Oral Microbiome Database (HOMD) was conceived and setup in 2005, providing vital information on the types of bacterial niches present within the oral cavity [45]. Within a recent period, 1,576 genomes and 784 different taxa within the oral cavity have been identifed and subsequently listed [49], of which FN species were representative of one of the most prevalent phyla within the adult oral cavity [50][51][52][53].
Although the establishment of polymicrobial flms as essential participants in the initiation and progression of periodontitis has been validated, some questions remain unanswered-the most important being how microbial dysbiosis and fuctuating microbial compositions within the oral cavity are able to instigate periodontal pathogenesis and if specifc microbial characteristics relate to other systemic diseases. More recently, the emergence of metatranscriptomics and metagenomics has permitted highthroughput analysis of microbial communities, thus illuminating some aspects of this conundrum.
Traditionally, microbial detection and identifcation involved the implementation of culture methodologies, including sample preparations, plate counts, and the isolation of singular bacterial colonies [54]. However, metagenomics is diferent in that it genomically analyses all microbial communities, evaluating functional relationships, population structure and diversities, and the interactions of these microbial communities within their specifc environments [55]. Te evident advantages of metagenomics are not only restricted to its ability to manufacture signifcant quantities of sequencing data approximately between 120 giga-bases-1.5 tera-bases/run [56], it has the capacity to interpret the functional diversities of microbial populations and discover diferent species/genes with certain functionalities [54]. More recently, an increasing number of articles have postulated that periodontal pathogens are a causative link to the development and aid progression of certain systemic diseases, including cancer [57]. Despite the   International Journal of Dentistry technology's positives, there are major shortcomings in the methodologies of several of the current studies investigating the efcacy of metagenomics, such as (i) inadequate sample sizes, thus afecting the efcacy of periodontal treatment on regulating periodontal microbial populations, (ii) study designs, (iii) sampling methods, and (iv) follow -up durations are all variable questioning its efectiveness in periodontal treatment evaluations [58].
In 2022, a review article examined the possible mechanisms by which oral microbial FN species were able to colonise the lactiferous ducts of breast tissue, via translocation into the systemic circulatory system [44]. A further study revealed that oral FN species were able to colonise cancerous tumoral growths via specifc attachment to Gal-GalNAc receptors displayed on the surface membranes of tumour cells [59], implying that oral FN species can reach other Gal-GalNAc-displaying tumours via the same mechanism. Terefore, as haematogenous Gal-GalNAc levels augment, female-specifc BC progression also accelerates [44].
Fap2 of FN species is a galactose-inhibitable adhesin involved in coaggregation and cell adhesion [18]. Results acquired "in vivo" from experimentations implemented on murine models revealed that FN-induced BC tumoral growths and their metastatic advancements were Fap2dependant and reversible with antibiotics [18]. A further study in 2019 involved the evaluation of the microbial abundances of over 40 bacterial species within 144 subgingival plaque samples [38]. One of the highest mean counts of infectious pathogens obtained from the samples included that of the FN species, thus drawing a strong association between oral FN species-induced chronic infammation as one of the risk factors for female BC [38].
A comparative study in 2016 undertook extensive analysis of microbial communities originating from female breast tissue samples of both benign and malignant growths. Te fndings deduced that there was a direct correlation between the microbial enrichment of FN species and that of female-specifc BC malignancies [39]. Te inference from these results implies that oral FN species have signifcant potential as biomarkers for BC afecting adult females, and by specifcally targeting oral FN species, it could signifcantly improve BC prognosis.
Contradictorily, a study in 2003 evaluating data from 11, 328 participants with a follow-up period between 11 and 21 years, including the NHANES I follow-up within the aforementioned time period, demonstrated no relationship between gingivitis or periodontitis and BC diagnosis in adult women [40]. A further study conducted in 2016 discovered no direct association between periodontal pathogens present within the oral cavity of the included participants and total/ site-specifc cancer incidences-including BC. (302) Tese  opposing fndings can be explained and could be a direct consequence of the following: (i) distinctiveness of the study design, (ii) whether periodontal assessment was factored into individual article assessments by the authors, (iii) author(s) adjustment for confounders, (iv) variable patient follow-up periods, and (v) patient sample sizes [41,42]. Nonetheless, the relationship between oral microbiota in its entirety and the possible utilisation of specifc microbial species in detecting and diagnosing female-specifc BC remains controversial.
An imperative aspect to consider is the importance of PD surgical procedures, the infuence of "fap designs" and utilisation of dental loupes on the risk of developing periodontitis. Conventionally, DFAs are the primary procedures implemented for direct root access and pocket elimination. Nonetheless, there are innumerable disadvantages such as membrane exposure, fap dehiscence, oedema, the absence of primary closure of interdental spaces, and bleeding [60]. With increasing importance being placed on SFA MIST and concomitant use of dental loupes, numerous articles concur that clinical outcomes of delicate tissues such as the gingiva are greatly improved as a result due to (i) reduced bleeding during operative procedures, (ii) minimal fap refections without periosteal incisions, and (iii) precise incisions promoting healing by primary intention via easy stabilisation of the undetached papilla [30,[61][62][63].
Preservation of intact papilla via MIST SFA promotes wound stabilisation permitting uneventful tissue formation and maturation [64].

Review Strengths.
Key strengths of this review included the spectrum of databases searched and the large number of included articles, thereby strengthening our statistical analysis. Additionally, all included articles and their reference lists were thoroughly examined by the authors, and cross-matched against the predetermined inclusion and exclusion criteria, thus enhancing the reliability of this systematic review. Furthermore, the use of the rigorous evaluator "AXIS Tool" for the scrutinization of information  Figure 3: Te PRISMA fow diagram outlines the search and selection process applied in preparation for this review. 8 International Journal of Dentistry presented in primary research articles permitted more indepth assessment of individual aspects of study design, providing a complete and overall qualitative analysis. Tis subjectivity permitted greater fexibility by incorporating quality of reporting concomitantly with risk of bias when assessing articles and providing a clear advantage over other appraisal tools such as the "Cochrane Risk of Bias Tool" which fails to address poor quality reportage [65].

Review
Limitations. Despite our best attempts, some review limitations have been identifed. For example, one included study within the meta-analysis was a defnitive contributor of result heterogeneity [43]. However, the exact reasons were unable to be precisely identifed. Additionally, there is a strong possibility that patient control selection bias was inadvertently introduced via the deliberate recruitment of individuals without gum disease to represent control groups in the included articles. Tere were evident discrepancies in defnitions of PD that varied between the articles examined, with some utilising various defning means to confrm PD diagnosis such as self-reported disease status, tooth mobility, and patient medical records, thus introducing article heterogeneity. Lastly, the relationship between oral FN species and their involvement in either the instigation/development of tumour stages in women were unable to be considered because of limitations of data availability.

Future Prospects.
Our search focussed on an array of observational and primary studies, literature reviews, and comparative and case studies. Despite our investigation having revealed a link between oral FN species and femalespecifc BC, to date there is still defcits of current data availability.
With this in mind, investigations into this feld with more focussed assessment objectives would be useful, thus taking the following into consideration: (i) IIF-"Identifcation-Isolation-Flag-up" of sub-types of FN species presence within the varying sections of breast tissue from a population of women with confrmed BC at diferent disease developmental stages (lowest grade-highest grade). Tis would allow for a precise analysis of microbial population counts and examination of the proportional activity levels of each subtype of FN species present. (ii) Te exact same procedure would be implemented in a population of women with confrmed diagnoses of varying oral infammatory conditions and at varying stages: (A) gingivitis (mild-moderatesevere) and (B) periodontitis (mild-moderate-severe).
We strongly believe that multiomics analysis [66] has immense potential for our proposal with respect to the discernment of complex relationships between the human microbiome and cancer risk. We suggest that integration of microbiome data with data obtained from other omics data of interest would permit understanding of causal factors for cancer development. Currently, microbiome multiomics data analysis is still challenging due to defcient tool availability [67]. To remediate this, further well-designed RCTs with lengthened follow-up periods would help confrm whether meta-transcriptomic/meta-genomic alterations are viable contributors to personalised periodontal therapies.
Our motion would aid DHCP's in the promotion of good oral hygiene maintenance (especially in adult women, as there has been previous mention of its necessity in a prior study) [42] and could revolutionise the feld of dentistry by promoting tailored treatments of high-risk patients/patients sufering from varying degrees of gingivitis and/or periodontitis, against the translocation of specifc oral FN species into the systemic system.

Conclusion
Tis systematic review and meta-analysis imply a signifcant relationship between oral FN species and their role in female-specifc BC pathogenesis, highlighting their biomarker potentiality. Our revelations raise awareness of the intricacies of this relationship with respect to adult female populations and could potentially help to reduce/prevent the risk of BC development worldwide, fundamentally transforming the future of both medical and dental prognostics.

FN:
Fusobacterium nucleatum BC: Breast cancer PD: Periodontal disease NHANES: National health and examination study DHCPs: Dental health care professionals ET 1: Endothelin 1 BDCIS: Breast ductal carcinoma In Situ RCT: Randomised clinical trial PST: Periodontal surgical trauma SFA: Single fap approach DFA: Double-fap approach MIST: Minimally invasive surgical technique.

Data Availability
All data have been provided in this article (main text). Additional data are accessible in the supplementary material section which can be accessed online.

Additional Points
Deeper understanding of how oral microbial imbalances potentiate/initiate/accelerate breast cancer pathogenesis in women would encourage more active discussions and collaborations between scientists, medical, and dental professionals. Te adoption of a fabricated collaborative personalised patient care ethos would be revolutionary in its creation of a more structured, informed, and supportive environment for both patients and their treating clinician(s)-potentially saving many lives. Tis article (1) critically analyses evidence regarding the relationship between oral F.N and female-specifc BC pathology. (2) Examines the link between endothelin (ET-1) molecules and oral FN species and their roles in infammatory cytokine activation, PD and BC pathogenesis. (3) Discusses surgical treatments for PD (specifcally periodontal fap designs) and the associated increase in risk of PD onset. (4) Illustrates the potentiality of oral FN species as biomarkers for BC pathology. (5) Compares the strengths and weaknesses of the presented evidence. (6) Raises awareness of the complex interactions of oral bacteria and infammatory cytokines at a cellular level as a novel approach for therapeutic targets, thus improving future PD and BC prognosis.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
Author 1 contributed to conception, project design, project supervision, data selection and interpretation, statistical analyses, and drafted and critically revised the manuscript. Authors 2 and 3 contributed to data acquisition and interpretation and critical revision of the manuscript. All authors have provided their fnal approval and agreed to be accountable for all aspects of the work.