Breast cancer (BC) is the most often diagnosed cancer in women and constitutes the second leading cause of cancer death among that group owing to its high mortality reported in less developed regions of the world [1]. BC is diagnosed in one in eight women in the Western world and is characterized by 90% 5-year relative survival rate and 84% 10-year relative survival rate [2], [3]. It is visible that through the years, clinical outcomes in BC have improved significantly due to past and ongoing research in this field regarding screening, diagnosis, and therapeutic strategies for overcoming the illness.

Risk factors of breast cancer include, most of all, aging, as the incidence of BC is significantly related to increasing age [2], and family history, as inherited susceptibility to the illness is connected with specific genes, comprising BRCA1, BRCA2, HER2, EGFR, and c-Myc [4]. Moreover, a variety of reproductive factors is considered to contribute to BC risk, including different categories: the category of age (age at menarche, age at first birth, age at menopause), category of non-human-influenced events (number of full-time pregnancies, history of spontaneous abortion) and category of human-influenced events (history of induced abortion, usage of birth control methods) [5], [6], [7], [8], [9], that are the main source of exogenous estrogen. That hormone, both of endogenous and exogenous origin, is important regarding BC risk. The ovary secretes endogenous estrogen in premenopausal women. Interestingly, ovariectomy was confirmed to reduce the BC risk [10]. On the other hand, the exogenous estrogen comes from two main sources, which are oral contraceptives mentioned before and hormone replacement therapy (HRT), the administration of which has been reduced due to adverse effects involving increased BC risk [11], [12]. Lifestyle also constitutes a significant risk factor. For instance, excessive consumption of alcohol was shown to increase BC risk by elevating the majority of estrogen-related hormone levels in the blood and thus activating the estrogen receptor pathways [13], [14]. Furthermore, numerous studies emphasize the influence of psychological stress connected with stressful life events on BC risk, and many examinations confirm the hypothesis that psychological factors might predispose to neoplasia [9], [15], [16]. Environmental factors are appraised to constitute the culprit of 70% of all malign tumors, however, when it comes to BC, that number varies from 90 to 95%. Among those factors, the role of BMI value cannot be omitted (Fig. 1) [17].

Obesity constitutes a growing problem in today’s society. It is defined as body mass index (BMI) exceeding 30kg/m2 [18]. Its importance as a major health problem cannot be neglected, especially in developed countries like the United States, where nearly 40% of adults are obese [19]. It could be expected that high BMI is another factor that leads to greater chances of developing BC, however, that is not always the case, and the impact of how obesity both raises and lowers chances of getting BC depending on the type of BC [18]. It has been reported that obesity is associated with a lower risk of getting ER-positive BC. That connection was observed mainly in white and Hispanic populations of the USA. The situation changes with triple-negative and inflammatory BC, both of which present significantly more aggressive courses. Studies showed that higher BMI is strictly connected with an elevated risk of developing both these diseases [20], [21], [22]. At the same time, other studies have shown that losing weight lowers the chances of getting BC [22], [23]. Additionally, it has to be mentioned that being obese leads to a higher probability of developing larger neoplasms and positive lymph node status, and it lowers the overall survival of the patients. Obesity leads to changes in adipose tissue structure. Its volume expands, which leads to higher oxygen demand that cannot be fulfilled. It creates a stressful environment in which more preadipocytes secrete proinflammatory adipokines and leptin [24], [25]. In obese adipose tissue, lipolysis takes place, releasing free fatty acids that activate NF-κB pathway. That leads to expression of inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-8 [26]. NF-κB activation also stimulates antiapoptotic genes and BC proliferation, invasion, angiogenesis and metastasis [27]. IL-6 and IL-8 also promote tumor progression, angiogenesis and chemotherapy resistance [28], [29]. All these changes show that obesity can directly affect the development of BC. During pregnancy, adipose tissue distribution changes. Accumulation of subcutaneous tissue is lower, however there is a higher accumulation of preperitoneal tissue[30]. It creates a hypothesis that describes changes to adipose tissue that could take place in accumulated peritoneal tissue, which could explain the heightened risk of developing breast cancer during the five-year period after pregnancy. This concept must be extensively studied to show if such a connection exists. It is also worth noticing that the connection between the amount of weight gained during pregnancy and the risk of developing breast cancer has been studied. It was revealed that gaining more than 15kg during pregnancy resulted in a 62% increase in BC risk compared to women who gained between 11 and 15kg. In addition, the highest presence of BC was reported in women who gained more than 20kg during pregnancy [30]. It confirms that body mass and size of adipose tissue are connected with the occurrence of BC, but more studies need to be conducted to fully understand the range of this relation. Reproductive factors should be examined more closely regarding their influence on BC occurrence, as pregnancy, abortion, and birth control methods influence homeostasis on many levels. The complexity of this impact will be described throughout the article. It should be underlined that two separate categories can be distinguished at this point: occurrences that cover natural physiology and pathophysiology not influenced by humans, such as pregnancy and miscarriage, as well as human-influenced interventions, such as abortion and birth control methods. Nevertheless, both categories influence BC occurrence and will be discussed individually. For instance, a full-term pregnancy increases short-term BC risk, as estrogen secretion, extraordinarily stimulated by pregnancy, is characterized by its growth-enhancing properties. On the contrary, pregnancy decreases the long-term BC risk, most probably because it induces terminal differentiation of the vulnerable mammary cells [31]. The hypothesis suggests that an interrupted pregnancy may raise the risk of breast cancer (BC) because the proliferation of breast cells during such specific, albeit normal, conditions fails to result in a protective effect from cell differentiation later on [5], [31]. The available research indicates that the risk of breast cancer may increase temporarily after a full-term pregnancy. This risk elevation is thought to be related to hormonal changes and breast tissue proliferation during pregnancy. Quantifying this increase, a meta-analysis has shown that the relative risk (RR) of breast cancer can rise by approximately 1.0 to 1.5 in the 5 to 10 years following a pregnancy compared to women who have not given birth. However, the exact increase can vary depending on individual factors such as age at first pregnancy and family history of breast cancer [32]. Considering the long-term decrease in BC risk after pregnancy, it was noted that over the long term, pregnancy and also breastfeeding [33] are associated with a protective effect against breast cancer. Studies have suggested that women who have had a full-term pregnancy have about a 20% to 30% lower risk of developing breast cancer in their lifetime compared to women who have never given birth. The protective effect increases with the number of full-term pregnancies [34]. The age of the full-term pregnancy also plays a role in altering the BC lifetime risk. Early pregnancy was confirmed to reduce that risk, whereas later, first full-term pregnancy increases it [35]. Early pregnancy, particularly before the age of 20, has been shown to reduce breast cancer risk more significantly, with reductions in risk estimated to be as much as 50% compared to women who have their first full-term pregnancy after the age of 35 [36]. Research on Danish women demonstrated that childbirths occurring before the age of 30 were associated with a decreased long-term risk of breast cancer. This reduction was observed for the first childbirth (approximately 5.0% reduction, with a 95% Confidence Interval (CI) of 2.1% to 7.8%), the second childbirth (approximately 6.4% reduction, with a 95% CI of 3.9% to 8.8%), and the third childbirth (approximately 9.4% reduction, with a 95% CI of 6.4% to 12.2%) [37]. Katz demonstrated that a single pregnancy at an early age protects women for 30–40 years, and this long-term protection is likely regulated by a relatively stable yet still modifiable method, such as epigenetic reprogramming [36]. The risk is believed to increase slightly with a later first full-term pregnancy due to less time for the protective effects of pregnancy-related breast tissue differentiation to take effect.

Understanding how early full-term pregnancy protects BC would help create innovative prevention and therapy strategies. Spontaneous and induced abortion seems not to alter the BC risk significantly, however, some research that contradicts this statement referring to increased BC risk in second-trimester abortion can be found, and therefore specific analysis of available data is necessary [8], [31]. Regarding birth control methods, an estimated hundred million women worldwide use oral contraception. However, its effect on BC risk is still not clearly understood [38]. Research shows that long-term combined estrogen-progestin hormone replacement therapy (HRT) and long-term oral contraceptive administration increase BC risk, whereas long-term estrogen replacement therapy and obesity in postmenopausal women are linked with mildly increased risk [7], [39]. The available studies indicate that women who use combined HRT (estrogen-progestin) for more than five years have a higher risk of developing breast cancer, with estimates suggesting a 15% to 33% increase in risk compared to non-users [40]. The definition of "long-term" in the context of oral contraceptives typically refers to usage for five years or longer. This usage has been associated with a slight increase in breast cancer risk, estimated at a relative risk increase of about 1.1, 1.2 and 1.9-fold [41]. For estrogen-only HRT, there was observed a significant decrease in BC risk by 23% [42]. Obesity has been linked to a moderately increased risk of postmenopausal breast cancer, with obese women (BMI > 30) experiencing about a 20% to 40% higher risk compared to those with a BMI in the normal range [43].

Considering these relationships, it's crucial to note that a complex interplay of genetic, hormonal, and lifestyle factors influences breast cancer risk. The percentages and relative risks mentioned provide a general framework but may vary based on individual and study-specific factors. Those conclusions suggest that estrogen alone can alter the risk of developing BC. Nevertheless, each factor that may influence hormone homeostasis should be considered while estimating BC risk.

Pregnancy constitutes both a risk factor for BC and a preventative agent against its appearance. The reason behind that phenomenon is that pregnancy is a complex process that affects a wide range of factors in a woman’s body, such as gene expression profiles and metabolism [44]. In order to understand the connection between pregnancy and BC, we search for answers to the following questions: How does the impact of pregnancy on BC occurrence vary depending on the age of the pregnant woman? Does ongoing pregnancy affect the treatment of BC?

Early pregnancy, which means pregnancy before age 20, reduces the prospect of developing breast cancer by 50% compared to a woman who has never given birth [45], [46]. In addition, every successive pregnancy lowers the risk by another 10% [37]. The situation is different when it comes to women aged 30 to 34. No evidence suggests that pregnancy in this age span lowers the risk of BC. However, being pregnant after age 35 has a negative effect as it increases the chance of breast cancer [45], [46]. Even though the presented facts constitute the long-term effect of pregnancy, no matter the age, race, or several pregnancies, the chance of developing BC and its malignancies is elevated within five years after giving birth [45], [46], [47]. Discussed factors imply that pregnancy activates several different processes that can impact BC prognoses negatively and protect women from developing cancer [44].

A strong correlation between early pregnancy, which means pregnancy under the age of 25, and a long-term reduction in BC risk has been discovered [37], [48]. The researchers have indicated that the 34th week of pregnancy is the developmental window for the cancer-preventive potential of gestation [37]. Nevertheless, despite such promising discoveries, some women who are pregnant and less than 25 years old do not experience the cancer-preventive potential of pregnancy and develop breast cancer [44]. However, we shall ponder the positive effect of gestation on breast cancer protection. As mentioned, childbirth under the age of 24 and even under the age of 25 provides women with a lifetime decrease in risk of the illness [49]. Moreover, it has been demonstrated that subsequent pregnancies after the first, early one only enhance the protective influence [50]. The described phenomenon is not only characteristic of humans, as it appears in experimental rodent models as well [6], [51], [52], [53], [54], [55], [56], [57], [58]. For instance, in one of the studies, two groups of rats were exposed to 7,12-dimethylbenz(a) anthracene (DMBA), a potent carcinogen. One of the groups consisted of virgin, cycling rats, while the other one comprised rats after a full-time pregnancy [6], [51], [52], [53], [54], [55], [56], [57], [58]. Rats that did not give birth were more susceptible to the carcinogen as they developed a DMBA-induced mammary cancer, contrary to those who had a full-time pregnancy. Results of the described experiment find an explanation in the interaction of DMBA with rapidly dividing epithelium that forms highly proliferative, undifferentiated structures called terminal end buds (TEBs) – carcinogen binds to the DNA of epithelial cells and that, combined with inadequate DNA repair, reinforces fixation of transformation consequently leading to cancerous initiation [59], [60], [61], [62], [63]. Interestingly, the pathogenesis of breast cancer in women remains similar to that of rodents that were induced by chemical carcinogenesis. It stems from the fact that Lobules type 1, from which originates the most common malignancy of BC, ductal carcinoma, bears a resemblance to TEB, which is also a site of origin of the same malignancy in rodents. Furthermore, epithelial cells from Lob 1 may be transformed, under in vitro conditions, by DMBA - which remains the same carcinogen able to induce mammary cancer in rodents [64]. Another crucial aspect of pregnancy's protective role in BC is the differentiation of breast tissue over a woman's lifetime. In women with normal menorrhea, breast tissue comprises three types of lobules – type 1, type 2, and type 3 [64], [65]. Lobule type 1 is undifferentiated, while Lob 2 and Lob 3 are, respectively, more developed. In sexually active, mature women, the composition of breasts is influenced by many factors such as age, with which comes several menstrual cycles, hormones, and specific imbalances such as the exogenous hormones supply and the physiological condition of pregnancy. It is essential to point out that during pregnancy and lactation, breasts are the most developed [48], which is attained by progression from Lob 2 and 3 ductile to secretory acini characteristic for Lobules type 4 that are fully differentiated. This is where the difference between those organs in parous and nulliparous women lies – breasts of the latter comprise a higher number of Lob 1, notably lesser Lob 2, and almost none of Lob 3 [65]. After menopause, the composition of breast tissue undergoes significant alterations. It is reported that during this period, the breasts of all women, whether they have given birth (parous) or not (nulliparous), are primarily made up of Lobule Type 1, as Lobule Types 2 and, in the case of parous women, Type 3, experience a decrease [65]. Despite that, the risk of developing BC is still much higher for nulliparous women than those who have given birth [49]. It indicates that Lobules type 1 may present important biological differences or be susceptible to carcinogens in varying degrees [65], [66]. That suggestion is worth investigating, especially after having observed that the prevalence of Lob 1 has been perceived not only in nulliparous women, both with and without cancer, but also it was similar in parous women battling BC [59], [66]. Consequently, the hypotheses arise that susceptibility to carcinogens is dependent on the degree of tissue differentiation [49], and parous women in whom breast cancer has developed might present an inadequate, lessened response to the influence the pregnancy hormones have on cells differentiation [65], which results in increased susceptibility to carcinogenesis. Crucial to those observations are cells forming Lobules type 1 that present high proliferative potential and are called Stem cells. In the breasts of nulliparous women and parous women with breast cancer, Lob 1 not only did not undergo the process of differentiation but also highly proliferative epithelial cells were concentrated, thus presenting susceptibility to carcinogens - these cells were called Stem cells-1. However, the cellular structure of breast tissue in early parous postmenopausal women free of cancer is quite different. Interestingly, the population of epithelial cells building Lobule type 1 is refractory to neoplastic transformation - they were called Stem cells 2 [49]. Moreover, they can metabolize carcinogens and are more effective in DNA repair than Stem cells-1. The presence of these cells makes them desirable protection from the development of breast cancer in early pregnancy [65], [66]. It was further stated that a certain degree of differentiation attained during early pregnancy changes the genomic signature, thus differentiating Lob 1 of early parous women from nulliparous women, and that is obtained by shifting Stem cells 1 to Stem cells-2 that are resistant to the damaging process of carcinogenesis [55], [59], [65], [66], [67]. However, if that shift is not completed, the neoplastic process may occur when the carcinogen is potent enough [49]. A described possibility might be the cause of BC development in a small fraction of early pregnant women – the differentiation cycle has not been fully completed. Regarding breast cancer risk, pregnancy-related hormones play a meaningful role, which has been visualized in a valuable study on rats. Mammary gland cells in young, which means from conception to early adulthood, rats are much more sensitive to carcinogens, and that period is called the high-risk susceptibility window [54], [59], [68], [69], [70], [71]. The endocrine system controls the response of cells after contact with carcinogens and the environmental impact on the animal [72]. These cells are located in mammary terminal end buds and are characterized by proliferative activity and are, therefore, called progenitor mammary stem cells [59]. When these cells exhibit carcinogen activity, they quickly expand and form intraductal proliferations that lead to ductal carcinomas in situ, establishing their transformation to mammary cancer stem cells [73], [74]. However, if the cells are not exposed to carcinogens and the rat conceives, the cells will become protected from cancer transformation by pregnancy hormones. This period is called the hormonal protection window [59], [75]. After implantation, the rat chorionic gonadotropin and rat placental lactogen are secreted. These two hormones stimulate mammary glands to transform from terminal end buds to alveolar buds and lobules [72]. In addition, another hormone – prolactin, together with oxytocin, completes the transformation of mammary glands. These transformations are responsible for genomic and structural changes in mammary glands, and because of that, the number of cancer cases in rats that were pregnant is much lower than in those who have never experienced pregnancy [61], [76], [77], [78]. However, when the mammary glands have been exposed to carcinogens during the high-risk susceptibility period, not only does the pregnancy not protect cells from carcinogenesis, but also it can enhance the chance of developing cancer [72]. Fifteen days after the administration of DMBA, rats that have been pregnant show a 100% chance of developing breast cancer [58], [79], [80]. The growth of tumours is sustained by breastfeeding; nonetheless, disruption to nursing induces tumour regression [79]. In that case, tumour growth is connected with the secretion of several hormones such as estrogen, progesterone, prolactin, placental lactogen, and relaxin [54]. The studies have not been conclusive, and the question of which of these hormones plays the most critical role in cancer development remains unanswered. Another study examined changes in gene expression and glycoprotein-induced immunomodulation during pregnancy on BC risk [81]. It is established that up to 238 genes are upregulated during pregnancy, and 48 genes become downregulated (Fig.2) [82]. The upregulations concern genes which are connected with immune responses. Genes like CCL5, CD48, and IL7R are upregulated during pregnancy, but after delivery, they decline to the same level reported in women who have never given birth. CCL5 gene induces activation and proliferation of NK cells, recruits leucocytes, and is connected with T cells [83], [84]. CD48 gene causes activation and proliferation of lymphocytes, dendritic and endothelial cells [85]. IL7R is responsible for the activation of T cells. Activation of these genes may result in an increased risk of breast cancer in a short period of time after giving birth [81]. Contrarily, other genes become upregulated in the pregnancy period, but interestingly, they persist in the organism even after delivery, although on a lower level than during gestation. These genes are inter alia CD38 and CXCL10 [81]. CD38 causes the activation of several immune cells, such as T cells, NK cells, and B lymphocytes [86]. On the other hand, CXCL10 is connected with chemoattraction, which causes anti-cancer and anti-angiogenic effects [87], [88], [89]. Upregulation and downregulation of these genes may have a critical impact on BC risk, however more studies addressing this particular issue must be performed so that we would be able to give a definitive answer [81].

During pregnancy, the immune system of women comes in contact with pregnancy-related antigens, which can be observed in breast cancer [90], [91], [92]. Furthermore, women who gave birth are additionally immunized against ovarian and endometrial cancer cells, yet such immunization is not present in nulliparous women [93], [94]. The most likely cause of this state is that the mother is exposed to foetal antigens that resemble the antigens of breast cancer - which protect against cancer. Transmembrane mucin glycoproteins, especially MUC1, are present in breast and ovary malignancies and play an important role in cancer propagation. MUC1 is located in the human epithelium in healthy patients, creating a barrier against pathogens [95], [96]. However, a structural difference exists between MUC1 in healthy and cancer tissue. In normal tissue, MUC1 is glycosylated with long core-2 glycans, while in cancer tissue, it is composed of shortened O-linked glycans [95]. Altered MUC1 becomes present in the organism during cancer development, in the placenta in the course of pregnancy, and in the lactating breast with mastitis [97], [98], [99]. The presence of altered MUC1 allows the organism to prepare the immune system to eliminate cancer cells, which could emerge later in life (Fig. 3) [95], [100]. There A study was conducted in which 149 serum samples were analyzed for the levels of IgM-anti-MUC1 and IgG-anti-MUC1 antibodies. Surprisingly, both levels were higher in pregnant women than in non-pregnant women. In addition, a better breast cancer prognosis was connected with higher MUC1 expression on cancer cells because cytotoxic CD3+/CD8+ T cells can lyse breast tumour cells that express this glycoprotein [100].

In studying the association of pregnancy with breast cancer, the influence of the placenta should not be omitted. It is an essential organ that allows a woman's body to support pregnancy. Its role is connected with the production of hormones such as progesterone, estrogen, placental lactogen, placental growth hormone, and chorionic gonadotropin [101]. Enumerated hormones can significantly alter women’s hormonal balance, and development can be altered because of breast cancer [99]. There is little information on the impact of estrogen on BC cells, however, the study suggests that high levels of pregnancy-related hormones can encourage the recurrence of cancer. At the same time, a higher survival rate is observed in women who got pregnant after diagnosis of breast cancer [102]. This phenomenon is called the “healthy mother effect” [103]. In in vitro environment, it has been discovered that placental cells can lower the number of cancer cells and decrease the expression of Er α [104]. Er α strongly impacts BC cells, endorsing cell proliferation and survival [105]. Additionally, parous women have two times higher ER β levels, which can negatively modulate ER α and reduce the progression of the tumor even in triple-negative breast cancer cells [106], [107], [108], [109]. Another substance produced by the placenta that can help fight BC is chorionic gonadotropin. This hormone's main production occurs during early pregnancy, but its level also rises towards delivery [110]. Chorionic gonadotropin has been called a natural chemopreventive agent, and its activity has been verified in experimental studies [111], [112], [113].

Not only do placental hormones have cancer-preventing properties, but special cells derived from the human placenta can also aid against cancer. One of the mentioned cells is human amniotic epithelial cells, which induce apoptosis in cancer cells and have an antiangiogenic effect [114]. They secrete thrombospondin-1, endostatin, and heparin sulfate proteoglycan; for this reason, it is deliberated whether to apply amniotic epithelial cells as a therapeutic anti-tumor strategy [115]. Although the described treatment appears promising, in various studies, cell lines unaffected by the treatment, such as the MCF-7 breast cancer cell line, have been detected [116]. In another study, treating cancer cells with placenta extract on mouse models caused inhibition of tumor growth and metastasis [117]. Even though most research on this issue raises hopes for a novel therapeutical approach, more extensive studies are needed to examine whether treating cancer with placenta extract is viable on a mass scale.

Pregnancy can extensively alter a woman’s metabolism, which can affect BC growth and metastasis. The changes can affect organisms negatively or positively depending on the pregnant woman's age. When pregnancy occurs at a young age, the risk of developing breast cancer becomes lower, and even if a woman develops cancer, the survival rate is higher [45], [46]. Being pregnant during BC treatment increases the chance of survival [102]. However, if a woman becomes pregnant after age 35, changes in metabolism that a few years earlier could protect the organism from BC now promote the development of cancer [45], [102]. Additionally, pregnancy raises the risk of developing BC in 5 subsequent years regardless of the mother’s age [45], [47], [102]. A complete understanding of how pregnancy influences BC requires more advanced studies.

The level of female hormones commonly changes throughout women’s lives for several reasons, and these hormonal fluctuations can lead to changes in breasts. Many of those hormonal changes occur during pregnancy, which can affect the chance of developing breast cancer later in life. Consequently, researchers have been investigating that matter over several decades to determine whether induced abortion or miscarriage (also known as spontaneous abortion) might impact breast cancer risk in later life.

Epidemiological studies on the safety of abortion and its impact on physical and mental health or fertility are still being conducted. Among those, the connection between the increased risk of breast cancer and induced abortion has been a subject of research for many years. Different reviews report conflicting information about the association of induced abortion (IA) with a heightened risk of developing BC. The majority of studies demonstrated no correlation. However, the ones showing small or significant connections between IA and BC can also be found [8], [118]. Most publications indicate that the influence depends on whether examined women are parous or non-parous. The available data suggest a positive association between BC and IA in parous women, whereas no association can be found for non-parous women [119]. It is important to note that there is a significant variation in the findings of studies on induced abortion, depending on whether they collect information prospectively or retrospectively. The relative risk is greater in retrospective records, but a non-significant association is validated. Observed variation may occur due to the greater propensity to disclose by women who developed breast cancer that they had IA in contrast to those with no breast cancer history [6], [120], [121]. It seems certain that more detailed studies are needed to determine the factual dependencies. Many publications suggest that current evidence is insufficient to support either the positive or negative association between IA and breast cancer risk [122], [123], [124], [125]. Therefore, unless solid evidence explicitly indicates one of the theories, monitoring women for BC with IA history should be continued.

One research on the described issue investigated the relationship between induced abortions and BC risk in BRCA1 and BRCA2 carriers. The study focused on BRCA2 mutation carriers with a history of induced abortion, indicating a lower risk of BC, whereas carrying a BRCA1 mutation did not appear to constitute a risk factor for BC development. The possibility of a protective effect of IA among women with a BRCA2 mutation who had two or more therapeutic abortions was considered, as in the BRCA2 group mutation, a 64% decrease in the risk of BC was observed. The association between the number of abortions and the risk of breast cancer among BRCA mutations has also been examined. The results of the study demonstrated a lack of association between the mean number of spontaneous abortions and BC risk in either BRCA1 carriers or BRCA2 carriers. Moreover, there were no differences in the rate of recurrent (three or more) abortions between cases and controls for either BRCA1 carriers or BRCA2 carriers (Fig. 4) [121].

Another research, a prospective cohort study, examined the association between lifestyle factors, reproductive factors, and the occurrence of BC, taking age at each abortion, current and past BMI, family history of BC, use of oral contraceptives, and parity into consideration during 10 years follow-up. After considering the impact of other BC risk factors, the hazard ratio for the development of breast cancer in the group that had one or more induced abortions was 1.01. Thus, the publication has also concluded that induced abortion is not associated with an increased risk of developing BC [126].

Nonetheless, some studies report a possible positive correlation between IA and breast cancer. A recent case-control study conducted in China analyses the influence of two types of induced abortion, surgical abortion (SA) and medical abortion (MA), on the occurrence of BC among pre-menopausal and post-menopausal women (average ages of 43.71 in case and 43.35 in control group) and post-menopausal women (average ages of 58.55 in case and 56.60 in control group) separately [8]. The research presents thought-provoking results, suggesting that having at least one MA affects the increase in the risk of BC in the pre- or post-menopausal group compared to the group with no IA history. As for SA, a considerable influence on BC development has been noted for post-menopausal women with three or more SA versus those who never had an IA. However, the most significant effect was found for women exposed to SA and MA. Whether it concerned the pre or post-menopausal group, those women had an 88% higher risk of BC than those without exposure to induced abortion (Fig. 5) [8]. Unfortunately, the study did not include the gestational age at the time of abortion, which may be an important factor requiring further research.

In conclusion, conclusions regarding the influence of IA on BC risk are inconsistent. Some studies find a slight increase in the risk of breast cancer development, whereas others report no association or even a decrease in BC risk. It is significant to note that the majority of studies on this topic clearly state that induced abortion does not increase a woman's risk of developing breast cancer [8], [118], [119], [120], [126]. However, further research is essential to negate the association or accurately estimate its significance.

Pregnancy loss is the major complication of early pregnancy, as at least one in three pregnancies ends in miscarriage. There is an evident correlation with future risk of myocardial infarction, cerebral infarction, hypertension, type II diabetes, and hypercholesterolemia. However, its etiology and significance are largely unknown [127], [128], [129]. Results from studies that focused on pregnancy loss and later risk of BC are diversified, though, the majority of them indicate no association. One of the studies investigated whether patients with a history of recurrent pregnancy loss have an increased risk of future female malignancies. The study by Mikkelsen et al. supported the conclusion that pregnancy loss was not associated with subsequent breast cancer development. The main strength of this study was the population size; the study group included over 28,000 incidents of invasive cancer, and an entire registry-based reproductive history confirms the study's validity. Among all observed Danish women, the authors do not confirm the association between several spontaneous abortions and later cancer development [130].

The occasional linkage with eventual cancer was found among women exposed to subtypes of pregnancy loss correlated with immune mechanisms, however, there is no clear trend indicating a robust positive association with site-specific cancers or cancer in general. The current studies cannot explain the modest increase in cancer risk in the primary repeat pregnancy loss group but hypothesize the existence of a common precursor increasing a woman's risk of both recurrent pregnancy loss and cancer or a mediating factor (changes in lifestyle or possibly by disrupting the maternal immune system and, most importantly, the ability to recognize cancer precursors) [130]. In addition, other studies that base merit on other values, such as size and nationwide coverage of the study population, objective recording of prior induced abortion status, matching controls for variables such as year of birth, place of residence, and socioeconomic status, and availability of information on important potential confounding variables, parity and age at birth of the first child [131], or comparing populations of different countries [120], present the data that do not support the hypothesis that miscarriage represents substantive risk factors for the future development of breast cancer.

Nevertheless, the described results are difficult to compare because the authors of the mentioned studies related only to the history of single spontaneous abortion. A recent study found recurrent (two or more) spontaneous pregnancy loss positively associated with future breast cancer. The most probable explanation is the resemblance of the pathogenetic mechanism in recurrent miscarriage and cancer, which may increase the risk of malignancy. A shared mechanism is an endocrinopathy involving insufficient progesterone production by the corpus luteum (luteal phase deficiency), which reduces the inhibitory effect of progesterone on future breast cancer development [132]. The epigenetic effect of aberrant expression of human HLA-G is another possible mechanism. Aberrant HLA-G expression is associated with RPL and is influenced by miRNA dysregulation. This miRNA dysregulation is also associated with cancer [133], [134]. Furthermore, it was suggested that the risk of BC in carriers of mutations in BRCA1 or BRCA2 is approximately 80 percent, but the individual risk may vary due to the influence of modifying factors. Reproductive agents have long been known to play an essential role in breast cancer risk in the general population. Several reproductive factors have been shown to influence the risk of BC in mutation carriers [121], [135].

Hormonal anticonception leverages the physiological effects of estrogens and synthetic progesterone to impede the occurrence of pregnancy. Progestins act by reducing the sensitivity of follicle tissue to FSH, resulting in the prevention of the emergence of a dominant follicle. Thus, the ovaries cease estrogen production, and the pituitary glands exert no LH exertion. Furthermore, progestins inhibit LH surge by direct impact on the gland. The lack of luteinizing hormone yields in the prevention of ovulation. Additionally, progestins create an impermeable barrier for sperm by inducing the thickening of the cervical mucus. The mechanism of action of estrogens involves the inhibition of LH and FSH release from the hypophysis while also bolstering progestin effects through upregulation of progestin receptors [136], [137]. The above-mentioned mechanisms represent only a subset of these agents’ effects on the system. In fact, the impact of these substances can be described as multifaceted. In this paragraph, we analyze the possible influence of birth control methods on breast cancer incidence.

The oral contraceptive pill (OCP) is the most commonly used reversible contraception form worldwide. It can be distinguished into two types: combined oral contraceptives (COCs), which consist of estrogen and progestin, and progestin-only pills (POPs), with only one active ingredient. Importantly, it must be highlighted that the history of BC and other neoplasms limits OCP usage. What is more, not only oncological conditions but also other kinds of health problems, such as diagnosed cardiovascular disease, often limit or even prohibit this type as well as other types of contraception. There are varied criteria that condition the type of contraception that can be recommended for certain medical conditions, the most well-known of which are The United States Medical Eligibility Criteria for Contraceptive Use (US MEC) and the UK version – UK MEC.

Unfortunately, the availability of data on oral contraceptive pills and their potential association with BC seems to be unclear. On one hand, certain studies posit an elevated risk of neoplasm attributable to OCP usage. According to one of the studies, OCP ever-users have higher (about 24%) chances of developing BC than non-users [138]. The data from other studies seems to advocate this correlation, albeit with variations in the reported risk [38], [139], [140], [141], [142]. A separate study by Hunter et al. scrutinized the impact of oral LNG on breast tumour development and identified an increased risk [143]. On the other hand, several studies show no such connection between oral contraceptive pills and the risk of BC [144], [145], [146]. The duration of OCP utilization emerges as a factor of significance in relation to the heightened risk of BC. However, definitive conclusions remain elusive. Some research states a gradual escalation in BC hazard with prolonged OCP use and time of OPC utilization [38], [139], while others assert an association only within the first years [141], and some studies fail to identify any such dependency at all [147]. Furthermore, nulliparous women taking OC appear to have augmented chances of developing BC. This might be attributed to the not fully developed mammary glands, rendering them more susceptible to carcinogens [138], [147], [148]. Additionally, one research group suggests an alternative explanation for higher BC findings in women using OCP. They posit that these women have more frequent contact with the health care system, leading to an increased number of diagnosed BC cases [140].

Currently, limited information is available regarding the correlation between using progestin-only subcutaneous implants and BC risk. A specific clinical study has not yet been conducted to assess this risk for using subdermal implants. However, several studies included people who used alternative forms of contraception in addition to subcutaneous contraceptive implants. One detected nine BC cases per 42,217 person-years of subdermal implant use, with an insignificant relative risk of 0.93 [139]. Another study assessed the use of implants and injectable progestogens in relation to the risk of BC. BC occurred in five of twelve women who received progestin implants. This study, however, included too few women with implants, which makes the results unreliable [149]. Another observational study conducted in eight developing countries over 5 years of follow-up in nearly 8,000 subdermal implant users (medial age 28.5 years) revealed 4 invasive and 2 in situ BCs, while a comparable number of women using IUDs or sterilized birth control showed 1 invasive and 0 in situ BCs. This represents a negligible incidence rate of 4.1 for invasive breast cancer [150]. Nevertheless, there is a lack of research aimed at examining the correlation between breast cancer and the use of subcutaneous implants with progestogen, so it cannot be clearly stated whether this method of contraception significantly increases BC occurrence.

In contrast to transdermal and oral ways, an intravaginal ring released less ethinyl estradiol, according to a study comparing the estradiol release of oral contraceptives, transdermal patches, and intravaginal rings [151]. An interesting prospective cohort study in Sweden examined Swedish women aged 15-34. In this study, researchers used two models of research, the first one of which contained numerous factors, such as the number of children, education level, and age at first full-term pregnancy, whereas the second one regarded both factors from the first model and additional ones: the body mass index (BMI) and smoking. In the first one, there were 50 registered cases of BC for 336 367 person-years for people that used patches or vaginal rings. Moreover, the absolute risk of using a patch or a vaginal ring was 14.9 %. In the second model, they found that there were 25 cases of breast cancer for 118 543 person-years for people that used patches or vaginal rings [141].

There is currently no published information on the use of vaginal contraception, increasing the risk of BC. However, it seems doubtful that it would significantly change the risk of breast cancer because it causes lower systemic estrogen metabolism [152].

DMPA contains long-acting progestogens and is intended for deep intramuscular injection. Progestogen-only injectable contraception works primarily by inhibiting ovulation. There is also an effect of limited motility of sperm. Small numbers limit studies investigating the relationship between DMPA use and BC. There is possibly a weak association between the regular use of DMPA and breast cancer. However, this risk reduces with time after stopping injections [153].

One of the most effective methods of reversible contraception is an intrauterine device (IUD), which is available in two varieties: nonhormonal (copper) and levonorgestrel hormonal (LNG) IUDs [154]. LARC (long-acting reversible contraception) includes methods of intrauterine contraception (copper IUDs and levonorgestrel intrauterine systems) and subcutaneous contraceptive implants. The copper IUD can be warranted for five or 10 years and can also be used as an emergency contraceptive. Levonorgestrel intrauterine systems (LNG-IUS) can be warranted for 3, 5, or 6 years. Those facts are very important as many patients misuse the described method, either by performing removal procedures themselves or not performing it in the recommended time, which might lead to fatal consequences [155], [156], [157], [158], [159], [160], [161].

When it comes to BC risk, analysis of available research lets us conclude that no significant correlation between the neoplastic disease occurrence and IUD is reported in premenopausal women however, when it comes to women aged 50 and more, the risk of BC is higher [162], [163], [164], [165]. Another study has also considered LNG-IUS usage, which showed that the risk in the postmenopausal women group is increased even more visibly if prolonged usage is reported [165]. Nevertheless, many studies claim that the connection between the described contraception method and tumor development is either insignificant or unclear, suggesting that further investigation is needed. No clear answer suggests to what extent breast cancer is related to IUD usage. Therefore, before using such an IUD, patients should be informed about the possible side effects and scientifically documented risks of using LNG-IUS for a long time.