HPV in Breast Carcinogenesis: Friend, Foe, or Fellow Traveler?

1. Introduction

BC is a significant public health issue and a primary cause of cancer-related mortality and morbidity among women [1, 2]. BC is one of the most prevalent malignancies in women, representing the sixth leading cause of cancer-related deaths and the primary source of cancer mortality among females. According to recent estimates, it has been projected that in 2020, there would be approximately 2.3 million new BC cases and around 685,000 related deaths worldwide. Over the past decade, there has been a steady increase in the incidence rate of BC [2, 3, 4, 5]. Interestingly, various risk factors are linked to BC, some well-known, while others are still unknown. Several variables can influence the development of BC, including early onset of menstruation (before age 12), never giving birth, late menopause (beyond age 55), exposure to substantial levels of ionizing radiation, frequent consumption of alcohol, and a diet heavy in fat [6].

However, several viruses have been implicated as potential etiological agents of BC. However, it is noteworthy that these factors only account for a fraction, varying from 20 to 50% of BC cases [7, 8, 9]. Among these viruses, bovine leukemia virus, Epstein–Barr virus (EBV), mouse mammary tumor virus (MMTV), and Human Papillomavirus (HPV) are reported as associated with BC [10, 11, 12, 13, 14]. Understanding the role of these viruses in the development of BC is crucial for effective prevention and treatment. Here, we outline the various molecular pathways that explain how HPV increases the likelihood of BC.

2. HPV genome and breast carcinogenesis

The Human Papillomavirus (HPV) is a member of the Papillomaviridae family, which includes over 200 distinct genotypes, of which 40 are transmitted via the genital tract. Notably, 16 of these genotypes have been identified as potentially oncogenic, with a particular association with cervical cancer. High-risk HPV types include 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 70. The oncogenic potential and transmission routes of these HPV genotypes are critical areas of study for developing effective prevention and intervention strategies [15, 16]. The genetic makeup of all HPV types includes a genome with eight open reading frames (ORF), transcribed from single-stranded DNA. The HPV genome comprises three central regions, which include early region (E), late region (L), and long control region (LCR). The LCR is 1 kb in length and lacks protein-coding regions. In the E area, there are six to seven ORFs, while in the L region, there are only two ORFs. HPV possesses conserved core genes, performs replication, and is involved in viral capsid development. However, there is a greater variation in E4, E5, E6, and E7 genes, which are involved in maturation, immune evasion, and the control of the cell cycle [17, 18], as shown in Figure 1.

Most HPV genomes, almost 86–100% within breast tissue, are incorporated with a low viral load between 0.00054 and 9.3 copies per cell [19]. HPV has a secondary role in tumors because of low viral titer. Different studies worldwide investigated a novel association between HPV and BC, while identification of HPV DNA (e.g., L1, L2, E1, E2, E6, and E7) in mammary carcinomas is highly inconsistent ranging between 0 and 86.2%, and it does not exhibit a correlation with the age of affected women [1, 28]. Therefore, molecular alterations in BC onset may be instigated via the “hit and run” mechanism. This conjecture implies that HPV plays a role in the initiation or facilitating of cancer development. However, in certain instances, due to the immune response vanishes from tumor cells before diagnosis [29]. The potential role of HPV as a modulator or contributor is still ambiguous and necessitates further research.

The carcinogenesis and chromosomal instability may be induced by HPV and host genome integration [30]. In BC tissues, the existence of E6 and E7 oncoproteins was confirmed, suggesting the potential involvement of HPV in BC progression. Specifically, E6/E7 mRNA was identified in 24 to 100% of HPV-positive BC specimens. Furthermore, novel E6/E7 fusion transcripts, namely E6^E7*I, E6^E7*II, were detected in breast tumors [19]. Substantial discrepancies were observed in HPV specimens, encompassing both HPV DNA and mRNA transcripts [31].

E6 degrades p53 through its interaction with E6-AP, a co-factor in the proteolytic pathway [30]. E6 exhibits functional and physical association with the telomerase complex [32]. E7 binds with pRb and retinoblastoma (pocket proteins), disrupts normal cell cycle mechanisms, and stimulates proliferation [19, 30]. The instability of the genome leads to normal cell transition to a malignant one. In an in vitro model, it is demonstrated that the expression of E6 and E7 oncoproteins causes mammary epithelial cell transformation. The cell cycle disruption is associated with cyclin-dependent kinase inhibitor 2A (CDKN2A or p16INK4A), and CDKN2A is not a marker for HPV infection in BC [33]. E6 and E7 interact with BRCA 1 and BRCA 2, which are tumor-suppressor genes [34].

When HPV E6 and E7 proteins bind to mammary epithelial cells, multiple biological mechanisms come into play. Proteins such as these upregulate the pathways by inhibiting pRb, p53, NFX1, and BRCA1 [35, 36]. Additionally, E6 and E7 proteins may stabilize the HER2 receptor, upregulate BCL2, and block apoptosis, all while stimulating the proliferation of BC cells [37, 38]. A3B may have its expression altered by HPV infection, and reactive oxygen species generation may be increased. There was an increase in the prevalence of APOBEC-associated mutation signatures in East Asians in BC (31.2 vs. 9.0% in Europeans and 4.2% in West Africans) [39, 40]. APOBEC mutagenesis, a phenomenon characterized by specific mutations in cancer genomes, can be triggered by APOBEC3A and APOBEC3B proteins. The pattern of mutations observed in bladder and BC patients is influenced by various factors, which can be categorized into hereditary and environmental elements [41]. In addition, HPV-induced STAT3 activation is associated with the production of genes for pro-inflammatory cytokines in cervical and BCs [42].

The viruses’ ability to cause cancer is related to several factors, including apoptosis evasion, deregulation of cellular processes, and persistent inflammation. BC cells proliferate more when there is ongoing inflammation, which is facilitated by cytokines such as interleukins (IL) and transforming growth factor beta (TGF-1) [43]. Moreover, HPV infection is connected to releasing IL-1, IL-6, IL-17, TGF-β, and TNF-α [44]. Furthermore, HPV synergizes with estrogen receptor (ER)-signaling pathways. Wu et al. demonstrated that, in conjunction with nuclear receptor coactivators, the HPV E2 protein increases the ERE-dependent transcriptional activity of Erα [45]. As a consequence, HPV-positive BC cells with strong estrogen signaling owing to ER gene amplification express the HPV oncogenes E6 and E7 more often, which accelerates the disease’s growth and progression [46].

3. Mechanism of HPV-induced BC development

There is a paucity of research available on how HPV causes BC; however, one idea proposes that HPV invades the breast gland through macrophages and lymphatic cells using systemic flow and that virion can also spread to other specific locations [47]. An additional hypothesis posits that HPV may have the ability to infect breast tissue, thereby potentially linking the breast’s exposure to external environmental factors and the development of BC. However, it is essential to note that this hypothesis requires further investigation and validation [48]. Sexual contact is one of the most common pathways for HPV invasion, and congenital HPV infection in children develops via placental or vaginal delivery [19, 49]. HPV enters breast cells via cell transport and endocytosis mechanism, and the alpha HPV genus is primarily involved in it [50]. The alpha-6 integrin protein is a receptor in cervix cells 51; however, in the breast, laminin-322 and alpha-6 integrin are involved in the morphogenesis of the mammary gland, and it is hypothesized that in case of a HPV infection, these proteins may promote tumor development [51, 52]. Integrin-mediated signaling pathways regulate neoplastic proliferation, programmed cell death, vascularization, and metastasis [53]. Upon cellular invasion, the viral DNA exists as an extrachromosomal element [54, 55]. At the same time, the mode of entry for LR-HPV is still unclear.

The potential role of extracellular vesicles (EVs), specifically exosomes, in disseminating HPV infection presents an intriguing hypothesis that may explain the increasing trend. This hypothesis is supported by the detection of blood-borne exosomes containing HPV genetic material in patients with HPV DNA-positive SCC of the middle rectum and BC, suggesting that EVs may play a role in HPV transmission and pathogenesis. However, further research is needed to confirm this hypothesis and elucidate the underlying mechanisms [56]. Notably, diverse cell types, tissues, and biofluids generate exosomes, which serve as cellular messengers encapsulating various biomolecules, including genetic material (DNA and RNA), proteins, and regulatory RNAs (non-coding RNAs) [57]. This exosome-mediated intercellular communication mechanism offers a plausible explanation for the non-contiguous spread of HPV infection, warranting further investigation [58]. Additionally, different studies have noted that oxidative stress could potentially affect the stromal compartment and the absorption of EVs [59]. By means of transmitting EVs positive for HPV from the primary site of infection to cells lacking the receptors of HPV, it is possible to induce the local proliferation of tumor cells. By means of in situ hybridization, the existence of HPV genome in stroma and epithelium was confirmed [60].

Both sexual and nonsexual ways can transmit the HPV. Most cases of genital HPV infection occur as a result of skin-to-skin or mucous membrane-to-muscle contact during oral or anal intercourse with an infected individual [61]. HPV can infect stratified epithelial cells once the virus enters the body by abrasions, lacerations, or epithelial surfaces. Figure 2 shows the several pathways that HPV can use to spread from an infected area to the mammary tissues. Hematogenous or lymphatic transmission of HPV particles from other parts of the body—particularly the cervix, neck, or head—to the breasts is one way [63, 64]. Sexual contact with the nipples or cutaneous micro-injuries in the breast region is another way that HPV can directly inoculate the mammary glands [61, 65].

The specific mechanism through which HPV gains access to the breast tissue is still unknown. The HR-HPV genotype was consistent in BC samples and squamous intraepithelial lesions of the cervix from the same patients, according to Lawson et al. [66]. Furthermore, the presence of squamous intraepithelial lesions associated with HPV was confirmed in BC samples collected from women who had BC. The scientists postulated that in cases of HPV-positive cervical cancer, the virus may potentially spread to the breasts through the bloodstream. It was suggested by Bodaghi et al. and others that HPV could spread via circulation since HPV DNA was detected in monocytes [64]. Researchers could not uncover evidence that HPV could infect monocytes or that the virus could propagate via the blood. HPV can affect basal cells within a stratified epithelium; however, its susceptibility is limited to cells situated in the more specialized epithelial layers. Who knows how HPV particles make their way from infected areas to the breast or anywhere else in the body—it’s just conjecture at this point. For virological reasons, explaining a circulation-based mechanism is challenging, as HPV multiplies in the squamous epithelium to evade immune detection. Circulating HPV DNA in the circulation may potentially be transferred to the breast, where it could be assimilated, according to one theory [67, 68].

De Carolis et al. emphasized the possible transfer of HPV genome from serum-derived extracellular vesicles (EVs) to TNBC [60]. The authors propose a potential role for HPV DNA from EVs in increasing the malignancy of BC, suggesting that HPV DNA may be transported from infected sites to the breast tissue via extracellular EVs. However, this hypothesis requires further investigation. One possibility is that certain sexual activities may cause minor skin injuries on the nipple or areola, providing a potential entry point for HPV to infect the breast tissue. HPV is most likely transmitted to the breast through direct contact with the skin or mucosal epithelium. Additionally, other potential factors, such as sexual transmission and EV transmission pathways, may also contribute to HPV infection of the breast tissue. Further research is needed to confirm these hypotheses and elucidate the underlying mechanisms [19, 46].

HPV has a particular affinity for infecting epithelial cells, which are responsible for lining different surfaces and cavities in the body. These may involve various parts of the body, such as the skin, respiratory tract, digestive tract, and reproductive organs. Epithelial differentiation is vital for the completion of the life cycle of HPV. It involves the specialization of cells in both structure and function [46, 69]. During the early stages of infection, HPV virions specifically attack the basal epithelial cells that have been exposed because of injury.

The virus can infiltrate these cells and integrate itself as a small episome in the nucleus, enclosed in a vesicle that contains the L2 protein. This process signifies the initiation of the HPV infection and lays the foundation for the subsequent replication and its gene expression. This process is unique to HPV and is not observed with other types of viruses [70]. After entering the host cell nucleus, the HPV genome goes through an initial amplification phase where it rapidly replicates multiple copies of itself within each cell. This process signifies the initiation of the HPV infection within the host cell and is crucial for the subsequent expression of viral genes [71].

4. Prevalence of HPV in BC

The global prevalence of HPV in BC ranges between 1.6% and 86.2% [7, 72, 73], even though other researchers found no HPV in these types of tumors [65, 74]. The incidence of HPV infection in BC did not appear to vary by region [19]. Comparing research is difficult, though, because of the variety of materials, which include fresh frozen tissue and PCR techniques with various primers used for HPV detection. Furthermore, it’s not impossible that contamination with earlier PCR products affected some of the preanalytical and analytical data. There has been reported geographic HPV transmission despite these restrictions. For instance, 32.42 and 12.91% of BC patients in Europe and Asia, respectively, were found to be HPV positive [75]. Moreover, 42.9% of BC population from North America and Australia had HPV, compared to 15.1% from South and Central America [46]. According to research that started with information from The Cancer Genome Atlas (TCGA) database and Australian BC specimens, 2.3% of BCs carried HR-HPVs. Next-Generation Sequencing (NGS) was then used to evaluate the data. Interestingly, benign breast specimens that tested positive for HR-HPV were linked to BCs that tested positive for the virus in the same subjects, according to the researchers. Furthermore, physiological activity of HR-HPV has been observed in British Columbia [76]. Bae and Kim [77] found that among those with positive HPV, the probability of having BC was increased by 4.02-fold (95% CI: 2.42–6.68). Similarly, Choi et al. found a link (OR = 5.43, 95% CI: 3.24–9.12) between BC and HPV infection [78].

Additionally, similar research by Ren et al. found a statistically significant correlation between BC development and HPV infection (OR = 6.22, 95% CI: 4.25–9.12) [79]. Notably, normal tissues did not show any evidence of HPV, but BC samples did [80]. In contrast to BC, the incidence of HPV infection in normal breast samples was significantly lower. Moreover, a higher prevalence of HPV infection was observed in BC compared to benign breast lesions, including fibroadenomas, fibrocystic changes, mastitis [46, 80], intraductal papilloma’s [81], and breast adenosis [65]. Furthermore, samples from fibroadenomas and neighboring normal breasts showed higher rates of HPV infection compared to samples from British Columbia (64.8%) [46]. Koilocytes, which are indicative of HPV-positive cells, were identified in BC cells using PCR [82]. Most HR-HPV types have been found in BC samples [19]. However, LR-HPV subtypes are reported in certain cases [83]. HPV16 is the most prevalent genotype in BC patients, accounting for 87.5% of cases, with HPV18 present in 12.5% of cases. Moreover, HPV16 was identified in 77.37% of BCs that tested positive for HPV, followed by HPV33 (13.64%) and HPV31 (9.09%) [84]. However, other papers state that HPV33 [85], HPV39 [86], or HPV51 [87] are widely frequent HPV subtypes in breast cancer. HPV DNA has been observed to be preferentially present in high-grade BC (II/III) [88].

Furthermore, grade II BC included the majority of HPV16 and 58, although grade III cancers had a higher rate of HPV18 infection [89]. According to the molecular classification (reviewed in [19]), all subtypes of BC, such as Luminal A, Luminal B, HER2-enriched, and triple-negative BC (TNBC), have HPV infection. However, HPV was shown to be more common in TNBC and HER2-enriched malignancies than in Luminal A and B types [90]. BC’s more aggressive biological activity is linked to HER2-enriched cancers and TNBC. Furthermore, compared to HER2-positive tumors, hormone receptor-positive BCs had greater HPV infection rates [81]. Furthermore, HPV was specifically present in HER2-negative Luminal B tumors; however, no statistically significant difference was seen between these cancers and other molecular subtypes, such as the Luminal B/HER2+ phenotype [83]. Surprisingly, HPV DNA was linked to increased lymph node invasion and greater rates of proliferation in Luminal A and Luminal B tumors, respectively. These results suggest a link between HPV infection and more severe types of BC illness. Nevertheless, no correlation with a specific molecular subtype was discovered [84].

There has been a long-standing debate over the precise etiology of BC that is associated with HPV. However, recent studies have shown that there is a significant connection between HPV infection and the development of BC. In spite of this, there are still a great deal of problems and difficulties that need to be solved in this area of study [62]. For detecting HPV, the majority of studies used either conventional or nested PCR using commercial primers for the L1 gene (capsid protein). They presented plausible reasons for false positive and false negative findings, as well as limiting variables linked to the diagnostic procedures utilized in those investigations, such as viral load and DNA/RNA quality [62]. This was done after the positive results were obtained. Primers were also used for the E6 and E7 genes, as well as sequencing processes. Only 13–15 of the 200 subtypes of HPV are high-risk, which are linked to a variety of malignancies [91]. The thorough meta-analysis conducted by Awan and colleagues revealed that the pooled prevalence of HPV infection among females diagnosed with BC was 25.6% (95% confidence interval (CI) = 0.24–0.33, I2 = 97%, τ2 = 0.0364, p = 0). New risk factors for the development of BC must be identified, as this result serves to highlight [62].

Following the stratification of the control group and the control breast tissues, Awan et al. discovered significant variability between the control and breast tissues [62]. The pooled frequency of HPV in BC tissues was found to be 26.2%, with overall odds of 5.55 (95% CI = 3.67–8.41, I2 = 38%, τ2 = 1.4878, p-value less than 0.01). The fact that the I2 value across subgroups was less than 50% and suggested that there was an acceptable amount of heterogeneity brought to light the significance of control selection. There have been reports of similar findings from other meta-analyses, which indicate that there is a substantial connection between HPV and BC. As an example, a meta-analysis of 37 case-control studies, which included 1728 controls and 3607 cases of BC, found overall odds of 6.22 (95% CI = 4.25 to 9.12, p = 0.0002) [79]. The odds were estimated to be 5.9 (95% CI = 3.26–10.67) in another study that included nine case-control studies [92]. Bae et al. found odds of 4.02 (95% CI: 2.42–6.68) [93] in a meta-analysis that included 22 different investigations. A meta-analysis of 10 case–control studies, which included 447 cases of BC and 275 controls, revealed that the presence of HPV positive was associated with an elevated risk of BC (OR = 3.63, 95% CI = 1.42–9.27) [75]. On the other hand, the consistency of several techniques of HPV detection, which suggest a much greater incidence of HPVs in BC than in control tissues [94], lends confidence to the hypothesis that there is a connection between the control group and BC.

The study and meta-analysis that Awan and colleagues conducted included 74 publications that were published throughout the last three decades [62]. In addition, the meta-analyses carried out in Europe, North America, and Australia by Simoes et al. [92] have provided an additional piece of evidence that supports their conclusions. In Iran, the prevalence of HPV infection among BC patients is notably higher compared to European women. This could be attributed to various factors, including differences in sexual behavior, cultural practices, or the prevalence of high-risk HPV strains in the region. Conversely, the prevalence is lower among women from North America and Australia, indicating that these regions might have more effective screening programs, higher HPV vaccination rates, or different patterns of HPV type distribution.

The report of up to 86% HPV infection rate in British Columbia is particularly striking. Such a high prevalence rate could point toward a lack of adequate screening or vaccination programs, or it could reflect a population with a higher risk of exposure to HPV. It’s important to note that this figure may not represent the general population but rather a specific subgroup within British Columbia that was studied. These findings underscore the importance of considering demographic and geographical factors when analyzing the prevalence of HPV infections. They also highlight the need for tailored public health strategies that address the unique challenges and risk factors present in different regions to effectively combat HPV-related diseases [48, 92]. The conclusion that can be derived from the numbers that have been published in the past is that about one in every four women have been diagnosed with HPV-positive BC [73, 75, 95].

The prevalence of HPV strains that were discovered in various groups was shown to be significantly different from one another [19]. HPV infections, which include HPV 16, 18, and 33, have been found in British Columbia [96]. HPV infections are frequently associated with genital atypical lesions and malignancies. Notably, HPV 11, 16, 18, and 33 were the most common types found in European women with BC, while HR or LR subtypes HPV 52, 59, and 83 were more prevalent in African women with BC [96, 97]. The HR subtypes of HPV, including HPV 16, 18, 31, 33, 35, 52, and 58, were investigated by Awan and colleagues [62]. The findings of the study revealed a significant association between all HPV types and an increased risk of BC (p < 0.05), supporting the current literature and suggesting that HPV infection may play a role in BC development and progression. Specifically, the frequency of HR HPVs in BC tissue was six times higher compared to normal and benign breast tissue controls. HPV-16 was the most frequently detected type in BC tissues, with an overall frequency of 9.7% (95% CI = 3.15–11.73, I2 = 0%, τ2 = 0.5766, p < 0.01). Additionally, HPV-18 was the second most prevalent type found in BC tissues, with a frequency of 6.6% (95% CI = 1.95–4.04, I2 = 0%, τ2 = 0.2734, p < 0.01). These findings suggest a potential role of HPV infection in BC pathogenesis and warrant further investigation [62].

The review and meta-analysis conducted by Awan and colleagues included 3156 publications that were published throughout the last three decades [62]. In order to establish the prevalence of HPV in BC tissues, they conducted a thorough analysis of 1223 investigations and examined 74 publications. However, they excluded 1130 studies since they were deemed insufficient. Meta-analyses carried out in Europe, North America, and Australia by Simoes et al. [92] have provided an additional piece of evidence that supports their conclusions. Interestingly, the prevalence of HPV infection was higher among patients with BC in Iran than among women from Europe, although it was lower among women from North America and Australia. It has been reported that up to 86% of people in British Columbia are infected with HPV, which suggests that demographic variables and geographical variances may be responsible for the discrepancies that exist across nations [48, 92]. The conclusion that can be derived from the numbers that have been published in the past is that about one in every four women diagnosed with BC are infected with HPV [75].

The HPV prevalence strains that were discovered in various groups were shown to be significantly different from one another [19]. HPV infections, which include HPV 16, 18, and 33, have been found in British Columbia [96]. These infections are often cited as etiological agents for cancer. It is interesting to note that HPV 11, 16, 18, and 33 were the most prevalent kinds among European women who had BC. On the other hand, African women were more likely to have HPV 52, 59, and 83, which were either HR or LR subtypes [96, 97]. The HR subtypes of HPV, including HPV 16, 18, 31, 33, 35, 52, and 58, were investigated by Awan and colleagues [62]. The results of their investigation indicated that all these HPVs were linked to an elevated chance of getting BC (p < 0.05). Their research lends credence to the current body of research and hints that the presence of HPV infection may have a role, either as a cause or a contributor, in the development and progression of BC. When compared to the frequency of HR HPVs in normal and benign breast tissue controls, the frequency of HR HPVs in BC tissue is six times greater [98]. Furthermore, the presence of HPV-16 in BC tissues was reported in 21 studies, resulting in an overall frequency of 9.7% (95% CI = 3.15–11.73, I2 = 0%, τ2 = 0.5766, p < 0.01). In addition, the second most prevalent form of HPV detected in BC tissues was HPV-18, which had a frequency of 6.6% (95% CI = 1.95–4.04, I2 = 0%, τ2 = 0.2734, p < 0.01) [62].

Awan et al. carried out a comprehensive study with the purpose of determining the prevalence and distribution of different HPV subtypes in breast cancer tissues from a variety of geographical locations. According to the findings of the study, the HPV-18 strain was considerably more widespread in Australia, but the HPV-16 strain was the most prevalent kind around the globe, including in Asia, America, Europe, and Africa. There were 45 articles that were examined, and 25 of them were from Asia. This indicates that the overall prevalence was 22.7%. The study also discovered that the prevalence of HPV in patients with breast cancer varied depending on the geographic location of the patients. Europe had the highest rate (39.1%), followed by Africa (31.8%), Australia (30.5%), and the United States (33%). In addition, this study indicates that the incidence of HPV in patients with breast cancer varies from area to region. These findings suggest that HPV prevalence in BC patients differs across regions, which could have significant implications for tailoring prevention and treatment strategies for BC caused by cervical cancer [62, 99].

Several factors could explain the regional disparity in HPV infection and its link to BC. These factors encompass sexual behavior, hygiene practices, vaccination history, screening routines, and socioeconomic standing [4, 5]. However, the high rate of BC in Asia attributed to HPV (22.7%) is because a considerable portion of its female population has multiple sexual partners, less condom usage, and restricted HPV vaccination access, healthcare disparities [5, 100] and cervical cancer screening [101]. Europe, conversely, exhibits a lower rate of HPV in BC cases (13.4%). This is because of the advanced health systems, increased knowledge on preventing HPV, and wider availability of the HPV vaccine [73, 95]. Additionally, the distribution of HPV subtypes and their carcinogenic potential can vary geographically. Specifically, HPV 16 and 18 are more prevalent and potentially oncogenic subtypes in BC tissues compared to other subtypes, although their distribution is not uniform worldwide. These variations in HPV subtypes could influence the risk of BC development across regions. Moreover, differences in detection methods, sample selection, and data quality and availability can impact HPV prevalence estimation in BC across countries and regions. However, the interpretation of findings may be complicated by factors such as the scope of research, accuracy of tests, and comprehensiveness of samples [62, 73].

Because the causal connection between HPV and BC cannot be definitively proven, there are still unanswered questions about the potential underlying mechanism. To prove that the virus is involved in the pathophysiological BC development, it is essential to address this issue, as the detection of HPV alone is not enough to establish this connection.

5. Conclusions

BC is a multifaceted and intricate disease that impacts a significant number of women globally. While the role of viral infections, particularly HPV, in BC etiology and progression remains contentious and unclear, mounting evidence suggests that HPV may be involved in BC development and progression. HPV may infect and transform mammary epithelial cells through various molecular pathways, and its interaction with other factors, such as genetic susceptibility, hormonal status, and immune response, may influence BC outcomes. Consequently, HPV detection and prevention in BC is a critical and complex task that necessitates further investigation and clinical application. Gaining a deeper understanding of HPV’s role in BC may offer novel insights into the pathogenesis, diagnosis, and treatment of this disease.

Conflict of interest

There is nothing to declare.