Breastfeeding and Reduced Risk of Breast Cancer in Women: A Review of Scientific Evidence Breastfeeding and Reduced Risk of Breast Cancer in Women: A Review of Scientific Evidence

Recent research shows that women who breastfed their children are at considerably less risk of developing breast cancer. Nonetheless, the results of other studies show that this greater protection only applies to pre-menopausal women. Based on the above results, there is still a certain controversy as to whether breastfeeding protects women against breast cancer. The main objective of this chapter is to provide a review of the scientific evidence regarding the relationship between breast cancer and certain aspects of pregnancy as breastfeeding period. For this purpose, it was conducted a systematic review in four databases (Web of Science, MEDLINE, Scopus and CINAHL), using the MeSH terms (Breast Feeding, Primary Prevention, Breast Neoplasms). The available scientific evidence justifies that breastfeeding for periods of over 6 months results in statistically significant reductions in the risk of developing breast cancer, the most common gyneco- logical tumor in young women. However, it remains to be studied further whether the observed risk reduction applies to women with inherited susceptibility to develop breast cancer. Apoptosis induced by a human milk protein 1995 Experimentalstudy A component of milk in a particular physical state – multimeric alpha-lact-albumin – is a potent Ca(2+)-elevating and apoptosis-inducing agent with broad, yet selective, cytotoxic activity.


Introduction
Breast cancer is the most common gynecological tumor in women [1,2]. Actually, the highest breast cancer incidence appears in high-income regions: population of North America, in population of Western Europe, Australia and New Zealand [3]. In fact, in developed countries, breast cancer is the leading cause of cancer death in women of 35-64 years of age. Each year, about 22% of new cancer cases diagnosed in women are breast cancer [4]. However, 17-36% of all breast cancers occur in women under the age of 40 [5].
The rapid increase in the incidence of breast cancer is a new social challenge as a result of a large number of risk factors, among them genetic causes and altered socio-economical conditions such as occupational exposure, rotating shift work and environmental factors (increased atmospheric pollution, sedentary lifestyle, and inadequate nutritional habits combined with an unbalanced diet). Other risk factors to be considered are lower age at menarche (below 10 years), late maternal age at first full-term pregnancy (over the age 30-40 years), and short periods of breastfeeding [6].
In the last years, different breast cancer prevention studies have been carried out internationally. Their main objective was to evaluate how a woman's chance of developing breast cancer was affected by breastfeeding as well as by pregnancy and childbirth. The results of these studies provide evidence about the influence of hormonal and reproductive factors in the development of breast cancer [7][8][9].

Methodology
A systematic review literature was conducted between March and April 2017; articles were collected from four databases (Web of Science, MEDLINE, Scopus and CINAHL), as well as from references in published research and reviews. The search strategy for potentially eligible studies included the following MeSH terms and combinations: Breast Feeding and Primary Prevention and Breast Neoplasms. The reference lists of included studies were also searched for additional eligible studies. Article inclusion criteria were as follows: (1) original studies and articles reporting on human females, (2) written in English and published in peer-reviewed journals, and (3) studies conducted in developed countries (Organization for Economic Cooperation and Development countries as defined by the World Bank). The following exclusion criteria were used: (1) studies using qualitative methodology, and (2) studies where analytic methods were not clearly reported. Titles and abstracts of retrieved studies were screened to assess whether inclusion criteria were met. Full texts were assessed when the abstract was found insufficient to make conclusions about inclusion. A total of 48 scientific articles were found, 41 in Web of Science, 2 in MEDLINE, 3 in Scopus, and 2 in CINAHL. Out of potentially relevant citations retrieved from electronic databases and searches of reference lists, finally, 34 articles were selected for this review ( Table 1) 2000 Case-control study The reduction in risk associated with duration of breastfeeding was not primarily due to breastfeeding the firstborn and more evident in women who were older (> 25 years) when they first breastfed and among women who experienced a recent full-term pregnancy. Reproductive events in adolescence have differential impact on the risk of breast cancer molecular subtypes in Japanese.
History of breast-feeding in relation to breast cancer risk: a review of the epidemiologic literature.

Literature review
The evidence with respect to "ever" breast-feeding remains inconclusive, with results indicating either no association or a rather weak protective effect against breast cancer.

Pregnancy
Early pregnancy has a protective effect against breast cancer [10]. Some of the mechanisms explaining the protective effect of pregnancy have been explored in animal models of breast cancer. Both early age (less than 20 years versus more than 30 years) at first full-term pregnancy and higher parity decrease breast cancer risk to half of the risk of nulliparous women [10]. Although the mechanisms are not entirely elucidated, pregnancy has been hypothesized to reduce the risk of breast cancer primarily through two mechanisms: firstly estrogen-induced mitosis may be suppressed by estriol, the main estrogen produced during pregnancy. Secondly, estrogen-induced mitosis may be suppressed by the hormone prolactin, whose levels are increased during pregnancy [11]. Then, high levels of estriol may protect women against the development of breast cancer [12,13]. However, there is somewhat less agreement concerning the role of prolactin in the disease. Different studies show a relationship between hyperprolactinemia and an increased risk of breast cancer in women [14,15]. The mechanisms potentially involved are: increased synthesis and expression of prolactin receptors in malignant breast tissue and a prolactin-induced increase in DNA synthesis in breast cancer cell in vivo [14]. Secondly, and according to Levine and Dolin [16], pregnancy reduces the risk of breast cancer because of the excretion of lipophilic carcinogens by the mother through the fetal fat and vernix caseosa.
Other studies have yielded conflicting results. According to Alberktsen et al. [17] in their study with 802,457 Norwegian women (20-56 years old), an increase in the diagnosis of breast cancer after full-term pregnancy was observed, particularly between 3 and 4 years after the delivery.
Hakansson et al. [18] and, more recently, Rough et al. [19] reported that human milk causes the vitro apoptosis or the programmed cell death of several varieties of cancer cells. On the other hand, the decrease of breast cancer risk due to prolonged lactation may be explained in part by the reduction of total number of ovulatory menstrual cycles and consequently cumulative ovarian hormone exposure [20]. Despite the scientific evidence available, there is an important controversy about the effect of hormones on the development of breast cancer. This is a complex task when we consider the complex etiopathogenic nature of breast tumors. Consequently, further studies are necessary in order to analyze this relationship [21].

Breast milk
Breastfeeding is still another research focus. An increasing number of studies have indicated that breastfeeding offers protection against breast cancer [22,23]. In the long term, the protection offered by breastfeeding is greater for premenopausal women, but also persists for postmenopausal women even after 50 years since the first lactation [24]. These protective effects of breastfeeding appear to be stronger the longer a woman breastfeeds her first child, as well as cumulative, such that increased lifetime duration of lactation over multiple children confers greater protection against breast cancer [25]. From a biological perspective, there are various explanations why breastfeeding seems to prevent breast cancer and why it appears to significantly benefit female health. One mechanism may involve a markedly reduced susceptibility of the fully differentiated mammary gland to carcinogens due to, at least in part, a decrease in proliferative activity of parous epithelium [26]. Other important changes are estrogen reduction and elimination through mammary fluid and the excretion of carcinogenic agents through the breast tissue during the breastfeeding process [27][28][29].
According to a study carried out by Cancer Research UK, the short duration of breastfeeding typical of women in developed countries makes a major contribution to the high incidence of breast cancer in these countries. The results obtained showed that the relative risk of breast cancer decreased by 7.0% for each birth in addition to a decrease of 4.3% for every 12 months of breastfeeding [30]. Despite such studies, many researchers are still skeptical as to the protection against breast cancer potentially afforded by breastfeeding. They claim that the data obtained until now are both insufficient and in many cases, inconsistent. Therefore, the influence of each birth should be considered when the relationship between breastfeeding and breast cancer is studied. Likewise, the reported breastfeeding duration is not very trusty, with values generally rounded to multiples of 6 or 12 months, particularly among women who had breastfed for long periods of time [31].
Nevertheless, a slightly lower rate of breast cancer was observed in women who breastfed their children for periods of over 12 months [32]. Of the women who had given birth, those who were cancer-free were more likely to have breastfed than those who subsequently developed breast cancer (79% as compared to 71%) [33]. However, a history of ever breast-feeding may be too crude an indicator, and it may be more important to demonstrate a dose-response association with increasing duration of breast-feeding in making causal inferences [34]. These results suggest an inverse relationship between breastfeeding duration and risk of developing breast cancer.
The decrease of relative risk´rate of developing breast cancer associated with breastfeeding did not change significantly for women in developed and developing countries, and did not change according to the age and ethnicity [31]. Other studies have analyzed breast cancer risk factors, including breastfeeding duration, in Asian and African populations. The results obtained about breastfeeding duration and risk of developing breast cancer between these populations are limited [35,36].
Additionally Michels et al. [37], in the Nurse's Health Study, in a retrospective review of breastfeeding duration in nearly 90,000 women, reported that, in comparison to never breastfeeding, the RR was 0.86 for fewer than 3 months of breastfeeding, 0.95 for 7-11 months, 0.86 for 12-23 months, and 1.11 for 24 months or longer. These results show the importance of the breastfeeding duration in reducing the risk of breast cancer.
Moreover, Zheng et al. [38], in the period 1997-1999 in Shandong, China, studied breast cancer risk in 404 women and in a control group. Their results show that for those women who breastfed their children for more than 24 months, the odds ratio was 0.46 (95% CI, 0.27-0.78) when compared with those women who breastfed their child for 1-6 months. These data suggest that prolonged lactation reduces breast cancer risk. Similar results were found by Hajian-Tilaki et al. [39], in their study with 100 women diagnosed of breast cancer and 200 controls. The authors conclude that duration of breast feeding was inversely associated with breast cancer risk. In another case-control study in Tunisia between 2006 and 2009, involving 400 breast cancer cases and 400 controls, the authors likewise observed an inverse association between breastfeeding duration and breast cancer risk [40].
Other review study developed by Nagata et al. [41], in which they identified three cohort studies and five case-control studies show similar results as described above. There was no significant association between the risk of breast cancer and breastfeeding according cohort studies analyzed. Nevertheless, in most case-control studies observed a statistically significant reduction in risk for women who ever had breastfed or for women with longer breastfeeding duration. These results again suggest that breastfeeding decreases the risk of breast cancer among Japanese women.
Despite the extensive scientific evidence available, there is still controversy about the effect of breastfeeding on the prevention of breast cancer. Consequently, more studies in different parts of the world are needed to analyze this relationship [42].

Conclusions
Breastfeeding for periods of over 6 months results in statistically significant reductions in the risk of developing breast cancer, the most common gynecological tumor in young women. However, it remains to be studied further whether the observed risk reduction applies to women with inherited susceptibility to develop breast cancer. Further studies must be conducted to focus on populations in which breastfeeding was common for relatively long durations, and should attempt to collect information on the errors in the reporting of lifetime duration of breastfeeding and other forms of complementary feeding. Meanwhile, this potential beneficial effect of breastfeeding for the mother should lead health professionals to