Breast cancer (BC) is a major public health issue that affects women all over the world. It is the most often diagnosed cancer and the second biggest cause of cancer-related deaths among women globally (1). Breast cancer occurs at different rates around the world, with Western nations having greater incidence rates than Eastern nations. However, due to lifestyle changes, an increase in longevity, and the adoption of Westernized dietary practices, the prevalence of breast cancer is quickly rising in low- and middle-income countries (1). Several studies have shown that several factors, including age, race, and socioeconomic status, genetic factors like BRCA mutations, hormonal factors like age at menarche, parity, and age at first full-term pregnancy, breastfeeding, and lifestyle-related factors like diet, physical activity, alcohol use, and tobacco use are all associated with an increased risk of breast cancer (2).

Understanding and treating carcinoma of the breast on a global basis depends heavily on epidemiology. Breast cancer is the most prevalent kind of cancer in women globally, and its effects on people’s health as well as the general population cannot be overstated (3). We can gather and analyze data using epidemiology to better understand the distribution, risk factors, incidence, fatalities, and variations in the occurrence of breast cancer. The rate of incidence is significantly higher among old-aged women and the median age of breast cancer diagnosis was 63 years from year 2014-2018, which has, increased to 69 years during the years 2015-2019. However, the mortality rate has been reduced by 1.1% during 2013-2019; improving the average life span of the population due to the accessibility and availability of better healthcare facilities and timely diagnosis which has a profound impact on longevity factors. In Pakistan, the incidence of BC is increasing as compared to other Asian countries and the average life span is 67 years, which is less than the Western population. Since 2019, nearly 4 million patients with breast cancer have been living in the United States and the number of metastatic breast tumors revolts to one and a half million by 2021 (4, 5). The ratio of recurrence is almost 20-30% among the women who are treated or considered free of disease (6).

Globally women have been affected by several types of breast cancer, which are differentiated based on hormone levels, aetiology, clinical screening and availability of various treatment options. Commonly, invasive breast cancer types are classified into estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor 2 (HER2). In Asia, the incidence of hormone-positive BC is relatively high as compared to other regions (7).

Determination of risk factors involved in the progression of breast cancer is especially important. Genetic factors such as gene mutations and family history are major threats to the development of cancer in first-degree relatives. Numerous biological processes, including histone modifications, polycomb/trithorax protein complexes, short non-coding or antisense RNAs, and DNA methylation, mediate epigenetic events. These various adjustments are intricately linked. The ability of genes to be expressed throughout typical stages of development is closely conditioned by epigenetic control (8). Histone deacetylases (HDACs) are a class of enzymes that play a critical role in the regulation of gene expression by modifying the acetylation status of histone proteins (9). Changes in the makeup of chromatin and the portability of DNA to DNA transcription factors can result from HDACs changing the acetylation status of histones, affecting the processes that lead to apoptosis (programmed cell death) and the cell cycle and altering the expression and function of hormone receptors such as the ER and PR, which may have an impact on hormone-dependent tumour growth. As a result, oncogenes may be activated or tumour suppressor genes may be silenced, accelerating the growth of cancer (10). Histone and non-histone proteins are acetylated by HDAC inhibitors (HDACi), which have an impact on gene expression, the advancement of the cell cycle, cell migration, terminal differentiation, and cell death. Understanding the anticancer mechanism(s) through which HDACi therapy drives differentiation in cancer may be crucial for understanding how GEF (guanine nucleotide exchange factor) protein regulation by HDAC inhibition influences cell differentiation (11). Age-related risks are closely related to the stage of menopause in women. Most women get affected with tumors at the post-menopausal stage (12). There is a strong association of breast density, obesity and hormonal imbalance with the incidence of breast cancer. Moreover, environmental and lifestyle risk factors, like toxic air pollution, occupational hazards, lack of physical activities, poor diet and smoking are contributing to the onset of BC (13). In leukemia and breast cells, HDAC expression and function are influenced by a variety of environmental variables. It has been demonstrated that environmental endocrine disruptors, change the expression and activity of the HDAC gene in breast cells (14). It is possible that altered HDAC activity plays a role in the emergence of leukemia, including acute myeloid leukemia (AML).

Chemicals known as endocrine disruptors prevent the endocrine system, which is in charge of producing and controlling hormones in the body, from operating normally. These substances have the potential to imitate or obstruct natural hormones, resulting in hormonal imbalances and possibly harmful consequences on health (15). Increased estrogen activity may result from exposure to endocrine disruptors, which may then promote the development of hormone-sensitive breast cancer cells. Certain endocrine-disrupting substances, especially bisphenol A (BPA) and phthalates, have been linked in studies to an increased risk of breast cancer. During the last several decades, there has been an increase in the prevalence of breast cancer worldwide. While many causes have contributed to this increase, endocrine disruptors are one cause for concern (16). Understanding the global epidemiology of breast cancer based on risk factors is essential for developing effective prevention and treatment strategies tailored to local populations. Therefore, this systematic review aims to evaluate the available evidence on the global epidemiology of breast cancer based on risk factors by systematically collecting recent published literature (2017-2022).

Patients with breast cancer have multiple risk factors associated with their disease (76). Depending on the characteristics of specific geographical regions, certain risk factors either modifiable or non-modifiable have variable influences on the health of women. Early identification of modifiable factors helps develop strategies to reduce the incidence of Breast cancer whereas other factors such as age, gender, and family history are not in an individual’s control to avoid breast cancer risk (77). Hormone positive breast tumor is quite common among Asian women. Figure 2 shows that approximately 50% of women have imbalanced hormonal levels, which increases the chances of BC development whereas in Europe and Africa, the estimated prevalence of BC due to hormonal abnormalities is 40%. Various risk factors contribute to the progression of breast tumors at various levels. All regions discussed in this review showed variable data on individual factors associated with the prevalence of BC all over the world. Presence of mutant genes (BRCA1 and BRCA2) can increase the incidence of BC up to 80% of women populations as compared to non-mutant genes (78). Few mutant genes (CHEK2, PTEN, CGH1, STK1 and PALB2) do not impose much influence on the occurrence of BC. Despite this genetic variability, a few genes (RAD52, OCT4, FASL, IGFIR, APE1, BARD1, IL4, and IL21) pose a protective impact and decrease the risk of developing BC. Chances of BC are significantly high if the patient has a positive BC family history even in men. Overall, the prevalence of BC in males is quite low but family history increases the risk in males as well. This trend is confirmed in various studies conducted in different regions of the world. We discussed association of various risk factors with specific geographical regions in the following sections.

A person’s demographic group or a particular subset of the population can have an impact on the occurrence, distribution, assessment, and management of breast cancer through certain characteristics. Demographic considerations can shed light on the patterns and trends in the incidence of breast cancer in various communities (79). Age, weight, and breast density are highly correlated with the incidence of BC (80). According to a study in Pakistani Asian women, younger females are more affected by BC and its prevalence increased from 70% to 130% among females aged 30 to 34 years and among the age group 50-64 years, the percentage prevalence increased from 23.1% to 60.7% (26) ( Table 1 ). Particularly, the incidence of metastatic BC and high-grade BC in young females has escalated in the past few years. The frequency, grade at being diagnosed, and available treatments for breast cancer can all be influenced by socioeconomic factors like income, education, and access to the hospital (81). Due to the socioeconomic problems in Asian countries, early diagnosis and timely screening is not accessible (31). People from rural areas have faulty beliefs and feel hesitation at the time of mammographic inspection (82). This reluctant behavior is a major reason for the increased incidence of BC at a young age. According to certain studies, married women might receive a better prognosis than single or divorced women (83). In adolescents, 86% of patients are diagnosed with invasive ductal carcinoma, 16.8% have luminal A and 30.5% patients have luminal B cancer. 30% of patients were affected by HER2+ whereas only 15% showed diagnosis with triple negative BC (32). Late diagnosis in developing countries drastically increased the progression to late stage tumor. In a recent study, Prevalence of stage III cancer was 62% whereas 24.8% patients were diagnosed with stage II cancer (47).

Breast cancer risk is heavily influenced by hereditary variables, and several genetic variants are known to dramatically enhance the risk of developing the illness. BRCA1 and BRCA2 gene mutations are the most well-known genetic changes linked to breast cancer. These genes are crucial for preserving the stability of the genetic material in the cell since they are involved in mending damaged DNA. The chance of developing breast and ovarian cancers is considerably increased by inheriting a deleterious mutation in either the BRCA1 or BRCA2 gene (84). An association has been observed between genetic mutations and the risk of BC. In Asia, Approximately 70% of patients have genetic polymorphism, DNA repair, overexpression of p53, presence of BRCA1 and BRCA2, and other hereditary characteristics ( Figure 2 ), whereas the risk of BC in other regions due to genetic mutation is comparatively low. High occurrence of breast cancer due to the genetic mutation in BRCA1 and BRCA2 genes in Asian women is directly related to first-degree relatives (85).

A complex interaction of factors, including genetics, way of life, socioeconomic circumstances, healthcare infrastructure, and cultural beliefs, characterizes the epidemiology of breast cancer in Africa. The female hormones progesterone and estrogen can affect the development of breast tissue and cells, and both their levels and activities are linked to an increased risk of breast cancer. A hormone called estrogen promotes the growth and upkeep of female reproductive tissues. High amounts of estrogen or continuous exposure to estrogen can raise the likelihood of breast cancer because it can encourage cell development in the breast. Imbalance of hormonal profile in the female population is the major risk factor for developing BC (86). Proliferation of cancer cells can be aggressive if estrogen and progesterone levels are not up to the mark. Breast cancer risk has been linked to long-term usage of combination hormone replacement therapy (estrogen and progestin) during menopause (87). Premenopausal and postmenopausal stages are highly linked with the occurrence of BC (88). Existing research on breast cancer in Africa is characterized by a limited collection of studies. According to the limited collections of studies conducted in Africa have been shown that 40% involvement of hormonal factors in the prevalence of BC. In addition, other factors; including Infections/Diseases, Air Pollution/Occupation, have been found to equally contribute to the occurrence of breast cancer within the African population. However, it is important to note that the lack of resources in many African regions poses significant challenges to collecting precise and comprehensive data. To gain a more comprehensive understanding of the distinct patterns of breast cancer in different African locations and to tailor therapeutic interventions accordingly, a more extensive and rigorous research effort is warranted.

Susceptibility of inherited mutations in America and Africa is modest however; nearly one-third of the female population of Europe and Israel is under threat of BC progression due to genetic mutations ( Figure 2 ). If a person contains dangerous mutations in breast cancer-related genes, genetic testing can reveal this. For the evaluation of risks, prevention tactics, and screening advice, this information may be essential (89).

Lifestyle modifications impart beneficial effects on women’s health. Women who are exposed to smoking, containing toxic aromatic compounds and consuming alcohol, are more prone to developing breast cancers (61, 63). Physical inactivity on a regular basis is linked to an increased risk of breast cancer. It has been demonstrated that regular physical activity lowers the incidence of breast cancer (90). Most of the population of America and Europe have a sedentary lifestyle and unhealthy eating habits (51) and the affected population with BC is 80% and 60% respectively ( Figure 2 ). Prevalence of lifestyle risk factors in other geographical regions is very low which may involve certain social and ethical problems (91).

Based on race and ethnic origin, the incidence rate is higher in black women as compared to white women (92). A recent surveillance and epidemiology study demonstrated that Asian Indian and Pakistani women who reside in the United States have a high degree of BC incidence ratio as compared to non-Hispanic white women (24). Based on age, young and late menopausal age are most affected by this life-threatening disease because of imbalanced hormonal profiles. Other factors including late pregnancy, use of contraceptive pills and hormonal therapies for conception alter the normal levels of estrogen and progesterone, which are the main hormones involved in the growth of BC.

Obesity is linked with majority of chronic diseases including breast carcinoma. A higher risk is observed in menopausal women who are obese and have a sedentary lifestyle as compared to the females having normal BMI (93). Unhealthy eating habits, consumption of Trans fats and dawn-to-dusk working hours affect the normal physiological processes of our body and increase the risk of developing cancer. Physical activities like walking and aerobic exercises help to reduce the threat of BC to a greater extent (94).

Air pollution, drug abuse and infections have a deleterious influence on the European population that affected 80% of the population ( Figure 2 ). Occupational hazards thrust including exposure to organic solvents and fumes of dangerous gases are more prominent causes of health problems in Europe (75). Moreover, noise pollution is also a crucial risk factor that is associated with the etiology of BC (75).

In addition to physical workouts, a healthy diet and consumption of essential vitamins reduce the risk of BC. Several studies have shown that intake of vitamin D with treatment has positive outcomes in cancer patients thus slowing the progression of the disease whereas its deficiency can increase the BC risk (95). Moreover, consumption of alcohol and smoking is linked with a higher incidence of BC and it is evident by various studies (69). Occupational toxic exposure and air pollution are also contributing factors in the occurrence of BC all over the world because of global climate alterations (96).

Quercetin (QCT), a flavonoid derived from many fruits and vegetables, is endowed with manifold biological properties, such as the ability to elicit a strong inhibitory effect on the growth of several tumor cell lines (97). Quercetin may aid in preventing DNA deterioration in cells and thwarting the formation of cancer cells by lowering oxidative stress (98). The BRCA genes’ expression may be affected by quercetin, perhaps improving their capacity for DNA repair (99). Research has been done on quercetin’s potential to lessen breast density, which could, in turn, reduce the risk of breast cancer. According to certain studies, quercetin can modify estrogen metabolism and affect hormone levels, which may affect the composition and density of breast tissue (100). QCT has been proposed as an auxiliary molecule when combined therapy, when given along with many chemotherapeutic medications, such as topotecan, cisplatin, and sorafenib, in the treatment of various malignancies (97). According to this review, genetic and hormonal risk factors contributed 40% toward prevalence of BC in women but lifestyle modification factors 60% associated with BC.

Obesity and breast cancer have a complicated and varied association. Insulin resistance and persistent low-grade inflammation are both linked to obesity. These elements can foster a body environment that is conducive to the growth of breast cancer (101). Due to increasing breast density, people may find it harder to identify breast tumors or abnormalities, which can delay diagnosis and treatment. Compared to non-obese patients, obese breast cancer patients are more likely to have a cancer recurrence and are at a higher risk of dying from the disease (102). Obesity has an inverse relation with menopause age that contributes to the development of Breast cancer (103). An observational study conducted in Europe and America explained that the risk of BC due to obesity was lower at premenopausal age as compared to postmenopausal age (53).

In Israel, breast cancer is by far the most prevalent type of cancer among women. Because of variables like longer life expectancies, altered reproductive habits, and lifestyle choices, prevalence rates have been continuously increasing. The mortality rate has been declining, nevertheless, in part because of breakthroughs in therapy, early detection, and screening techniques. Women between the ages of 50 and 74 can receive mammograms through Israel’s national breast cancer screening program. The goal of this initiative is to identify breast cancer early, when it can be treated more successfully. The decreasing mortality rates have been attributed to routine screening and early diagnosis (104). Particularly among Ashkenazi Jewish women, Israel’s population is distinct in that some genetic variants are relatively common. This population has a greater prevalence of BRCA1 and BRCA2 gene mutations, which increases the chance of getting breast and ovarian cancer and reported elevated carrier frequency of 0.9% in the Ashkenazi Jewish population, a specific BRCA1 mutation known as 185delAG is also occasionally seen in non-Jewish patients with a distinct haplotype (105). Breast density is another factor associated with the incidence of BC as females with dense breasts are at a higher chance of developing BC as compared to those with less dense breasts (72). Early diagnosis by mammography is significantly difficult in dense breasts, which leads to the progression of late-stage BC. On the other hand, certain diseases such as diabetes, hypertension, insulin intolerance, multiple sclerosis and polycystic ovary syndrome (PCOS) also increase the risk of BC (106). Our data showed that in Israel demographic and genetic factors are predominant (40%) among the population as compared to other risk factors, which associated with occurrence of BC only 20% ( Figure 2 ). For the most up-to-date details about breast cancer epidemiology in Israel, it is crucial to study the most recent sources, including Israeli health authorities, cancer registries, and research organizations.

This paper has reviewed studies of incidence, prevalence, and risk factors for breast cancer in India, Pakistan, Kazakhstan, Turkey, USA, Europe and the United Arab Emirates. The evidence shows that diet, obesity, and genetic factors, such as BRCA mutations and DNA repair gene polymorphisms vary from region to region. These findings emphasize the need to be aware of the particularities of each region of the world with respect to breast cancer risk. This will facilitate early detection and improve prognosis. Our study provides valuable insights into the epidemiology, risk factors, and outcomes of breast cancer in various populations and highlights the need for further research and intervention efforts to reduce the burden of breast cancer in these regions.

Not all world regions were included and study methodologies varied. In addition, the traditions, customs, and genetic backgrounds of the residents of different geographic regions is only superficially known. Thus, more specific research is needed that specifically target distinct populations or examine particular risk factors in order to enhance the comprehensiveness and accuracy of findings.

The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.

AR played a major role in the literature search, collecting and screening of abstracts, full-text articles, data extraction and quality assessment of the included studies and prepare the first draft of the manuscript, AK provide the Idea and design for systematic review, supervised and guided AR in data collection and reporting and review and revised the manuscript. FA and ZA: screening of abstracts, full-text articles, data extraction and quality assessment of the included studies and revision of the manuscript. MA, MK, MS, RA: critical revision of manuscript and resolution of discrepancies. All authors made significant intellectual contributions and approved the final version of the manuscript.