Keywords
breast cancer - breastfeeding - breast cancer risk - HAMLET
Schlüsselwörter
Brustkrebs - Stillen - Brustkrebsrisiko - HAMLET
Introduction
In the advancing and developed world breast cancer is a significant global challenge,
impacting women [1]
[2] “considerably”. Each year, around 2.3 million breast cancer cases are diagnosed
worldwide, contributing to a 19.6 million Disability-Adjusted Life Years (DALYs) for
women [3]. Each year, around 2.3 million breast cancer cases are diagnosed worldwide, contributing
to a 19.6 million Disability-Adjusted Life Years (DALYs) for women [4]. Additionally, a rise from 140 to 170 thousand is expected to be observed in metastatic,
violent breast cancer cases by the year 2025 [5] Contrasting to these alarming figures, progress pace
in reducing breast cancer mortalities has been slowed down over the past two decades.
In the reduction of risk of breast cancer, breastfeeding comes in light as a key aspect
[6]. A meta-analysis performed by Bernier et al., in 2000 including 40 studies showed
that breastfeeding reduces breast cancer risk [7]. Another meta-analysis performed by Zhou et al. in 2015 which included 27 studies
and involved 13907 breast cancer cases also came to the same deduction [8]. On the other hand, a systematic review, which included 31 studies between 1999
and 2007, also found breast cancer to be inversely proportional to breastfeeding [9]. Another systematic review including 65 studies between 2005 and 2015 also
came to the same conclusion [10].
The total studies from the above-mentioned meta-analyses and systematic reviews, when
pooled and organized based on distinct world regions, as shown in [Fig. 1], provide insight into the heterogeneity among the varied populations studied alongside
the global implications of the inverse correlation between breastfeeding and breast
cancer.
Fig. 1
Organized studies from the above-mentioned meta-analyses and systematic reviews based
on distinct world regions (Fig. based on data from [7]
[8]
[9]
[10]).
Mothers and infants both benefit from breastfeeding. Immediate advantages which are
experienced by breastfeeding mothers include reduced risk of postpartum depression,
postpartum weight loss and lactational amenorrhea [6]
[11]. A decreased risk of breast cancer, osteoporosis, type 2 diabetes, rheumatoid arthritis
cardiovascular disease, and ovarian cancer are the benefits that mother receives in
the long run [11]
[12]
[13]
Breastfeeding for over a year is shown by studies to decrease the risk of invasive
breast cancer by approximately 4.3% [14]. All breastfeeding mothers have the risk of developing breast cancer lowered to
11%, while mothers nursing their babies for over a year experience a 26% reduction
in breast carcinoma development [11]. Despite the well-known advantages of breastfeeding, breastfeeding rates around
the globe remain below recommended levels [13]
[15]. Various biological, psychosocial, and social factors contribute to the lack of
change in breastfeeding status. Common reasons for discontinuing breastfeeding prematurely
include insufficient milk supply, maternal fatigue, and returning to work or
school. Socioeconomic factors like a mother’s education, income, and lifestyle also
influence breastfeeding [13]
[15]. To enhance breastfeeding rates worldwide, organizations like United Nations International
Children’s Emergency Fund (UNICEF) and World Health Organization (WHO) are making
strides towards it. This review seeks to explore how disruptions or discontinuation
of breastfeeding can increase the risk of developing breast cancer. Understanding
these mechanisms, we aim to promote breastfeeding in both low and high-income as a
natural protective measure against breast cancer.
Breast Morphology
Breast development in females bodies the mammary glands essential for milk production,
which is crucial for the nourishment of newborns [16]. A comprehensive understanding of breast anatomy is vital for grasping its intricate
links with breast cancer. The surface anatomy of the mammary gland encompasses the
areola and nipple, collectively forming the Nipple-Areola Complex (NAC). The nipple,
highly sensitive due to its rich nerve supply, is penetrated by 15 to 20 lactiferous
ducts on average, with some nipples having more ductal orifices [17]. Surrounding the nipple is the areola, a dark-hued area replete with sweat and sebaceous
glands, producing oils that help prevent nipple cracking. The NAC has a key role regarding
milk ejection during breastfeeding and it can be influenced by hormonal changes [18]
[19]
[20]. [Fig. 2] shows mammogenesis from embryo to lactation, followed by involution. Subsequent
observations indicating an elevated risk of developing cancer in the breast not suckled
during lactation in women who nursed from only one breast seemed to further endorse
a potential link [21]. In their case-control study involving 528 breast cancer cases, Freudenheim et al.
discovered that being breastfed was linked to a decreased risk of breast cancer (RR = 0.74,
95% CI 0.56–0.99). This reduction in risk in observed for both pre- and postmenopausal
breast cancer amongst women who had breastfed [22].
Fig. 2
Mammogenesis from embryo to lactation, followed by involution.
Review
Lactation induces resistance to carcinogens
Studies suggest that using medication to suppress lactation did not show any association
with the risk of postmenopausal breast cancer, irrespective of the age at first use.
Moreover, women who mentioned insufficient milk supply as their reason for not breastfeeding
did not exhibit an elevated risk of breast cancer when compared to women with a sufficient
milk supply, after accounting for the total duration of lactation [23].
Studies, coupled with findings from various reports, cast doubt on the idea that the
apparent protective impact of lactation is linked to a heightened risk among women
who cannot lactate. Furthermore, there is no indication from this study or recent
studies to support an increased risk of breast cancer among those who use lactation
suppressants [24]
[25]
[26]
[27]
[28]
[29].
Research involving lactating rats and mice suggests that they demonstrate a certain
resistance to the effects of chemical carcinogens when compared to their non-lactating
counterparts [30]
[31]. This resistance is thought to be a result of lower rates of DNA synthesis during
lactation or an increased elimination of carcinogens by the mammary glands during
secretion [30]
[31]
[32]
[33]
[34].
The protective role of suppressing ovulation and prolonged breastfeeding against breast
cancer
Among the various mechanisms suggested to account for the beneficial effects of lactation
on breast cancer risk, it is still uncertain which ones precisely align with epidemiologic
observations. The suppression of ovulation that comes with prolonged breastfeeding
might play a role in diminishing exposure to the cyclic hormones associated with reproductive
life. Notably, in studies that have identified an impact of lactation, a prolonged
duration of breastfeeding emerges as the most influential predictor of breast cancer
risk. This highlights the significance of exploring the ovulatory suppression mechanism
in order to understand the potential protective effects of lactation against breast
cancer [35].
The initial suggestion of an association between lactation and breast cancer dates
back to Lane-Claypon, who noted that women with breast cancer frequently reported
difficulties in breastfeeding [20]. Subsequent observations indicating an elevated risk of developing cancer in the
breast not suckled during lactation in women who nursed from only one breast seemed
to further endorse a potential link [21]. In their case-control study involving 528 breast cancer cases, Freudenheim et al.
discovered that being breastfed was linked to a decreased risk of breast cancer (RR
= 0.74, 95% CI 0.56–0.99). This reduction in risk was observed for both pre- and postmenopausal
breast cancer amongst women who had breastfed [22].
Breastfeeding and the risks of breast cancer in different subtypes
During breast cancer, certain protein hormone receptors serve as indicators of breast
cancer due to an overexpression leading to speedy proliferation, mainly being the
Estrogen (ER), Progesterone (PR) and the Human Epidermal growth factor Receptor 2
(HER2) [36]. According to a research study, increased parity and breastfeeding history emerged
as the strongest protective factors among luminal A BC. Conversely, earlier menarche
and later FFTP elevated the risk. For TN tumors, both later menarche and prior breastfeeding
exhibited protective effects [37]. Scientists looked at 38 studies on breast cancer risk factors in women before and
after menopause, including Caucasians and Asians. They found that known risk factors
mostly apply to a specific type of breast cancer called luminal A (ER+ and/or PR+,
HER2−), while distinct risk factors
may be associated with other subtypes [38]. A recent study has shown that ever breastfeeding or longer breastfeeding was associated
with low risk and protection for HER2+, TN, luminal A and luminal B type breast cancers
[39]. A meta-analysis of 15 studies of varied origin suggested higher parity and younger
age at FFTP to be associated with a reduced risk of luminal BC [40], while breastfeeding exhibited a protective effect for both luminal and TN BC [41]. In a study based on 890 breast cancer participants, IHC staining revealed that
a little or no breastfeeding along with a high waist to hip ratio was related to most
of the TNBCs [42]. The results observed for younger women were of varied nature as some showed relation
of age of menarche with protection against TNBC, while others did not. However, reproductive
risk factors for hormone-dependent tumors (ER+) align with previous findings showing
significant protection against ER+ and ER− tumors with breastfeeding durations lasting
up to 6 months and 12 months respectively [37]. When the effect of breastfeeding was studied together with the number of parities,
a strong protective effect was shown for women who breastfed two or more children.
In addition old age of menarche was protective for both ER− and TNBC [43]
[44]. However, conception or higher number of parities did not associate with any risk
of ER− and TNBC [37]. Similar results were observed in a later study, indicating strong protection against
ER− and TNBC with longer breastfeeding durations (12 months) and even a shorter duration
of 6 months to exhibit protection against ER+ breast cancers [45].
Epidemiology of breastfeeding and breast cancer
Research has uncovered a link between breastfeeding, one of the modifiable risk factors,
and the susceptibility to breast cancer [46]. These investigations shed light on the intricate interplay between the breastfeeding
duration, the number of pregnancies (parity), and the age of menarche (first menstrual
cycle), all of which bear significance in the context of breast cancer etiology and
its prognostic implications [46]. Epidemiological investigations commonly consider two key factors, alongside the
duration of breastfeeding, when exploring the association between breastfeeding practices
and the risk of breast cancer: the age of females and their pregnancy (parity) status
[47]. This hormonal exposure is intricately linked to the number of times the cells of
a
female breast undergo proliferation during each menstrual cycle, thereby influencing
the potential for breast cancer development. Moreover, the number of pregnancies a
woman experiences is related to the frequency of her breast preparation for lactation,
exposing her to the concomitant hormonal and physiological changes. Notably, when
investigating the breast cancer risk associated with women’s reproductive behaviors,
a study among the Chinese population revealed a higher prevalence of Luminal A type
breast cancer compared to the Triple-Negative Breast Cancer (TNBC). Additionally,
the more aggressive forms of breast cancer, such as Luminal B type and HER2-enriched
BC, were found to be less prevalent among women who adhered to regular breastfeeding
practices. This study also underscored the significant protective role of early age
menarche and the increasing number of pregnancies towards mitigating the risk of breast
cancer [48]. Women, who are reluctant or unable to breastfeed, experience the more aggressive
‘Parity Associated Breast Cancer’ (PABC), such as TNBC. Importantly, a significant
50% reduction in PABC risk has been noted in young women who engaged in longer durations
of breastfeeding, reaching up to 12 months during their lifetime [49]
Pregnancies, breastfeeding, and breast cancer risk
Breastfeeding was found to be a risk-reducing factor for breast cancer, however, certain
variations exist across different cancer subtypes. A negative correlation was found
to exist between the duration of breastfeeding and the breast cancer risk. A comprehensive
meta-analysis, which integrated findings from six significant studies and applied
the Preferred reporting items for systematic review and meta-analysis, (PRISMA) flowchart
methodology, confirmed strong connections between extended periods of breastfeeding
and a reduced risk of breast cancer [50].
Estrogen and progesterone, recognized as key factors driving breast cancer, promote
the proliferation of cells in breast tissue. The levels of these hormones undergo
substantial changes during pregnancy and lactation, which have a significant impact
on the development of the mammary glands [51]. Throughout this process, two essential hormone groups play a critical role: reproductive
hormones (estrogen, progesterone, prolactin, placental lactogen, oxytocin) and metabolic
hormones (growth hormones, glucocorticoids, thyroid hormones, insulin). Estrogen and
growth hormone influence ductal morphogenesis, whereas progesterone, placental lactogen,
and prolactin initiate alveolar development. Lactation involves lactogenesis 1 and
2, where progesterone inhibits active milk secretion in the former, and prolactin
becomes prominent in the latter. Prolactin regulates milk secretion, and oxytocin
controls milk
ejection [52].
Prolactin, a hormone primarily synthesized by the pituitary gland and various other
tissues, is linked to an increased risk of breast cancer, particularly in postmenopausal
women. While it does not directly impact cancer cells, it encourages undifferentiated
breast cells, making them more vulnerable to becoming cancerous [52]. Additionally, prolactin fosters a pro-cancer environment by inciting inflammation,
thickening breast tissue, and elevating cancer risk, particularly in estrogen receptor-positive
(ER+) breast cancers where prolactin receptors (PRLRs) are abundant. Efforts to block
PRL receptors or reduce PRL levels for breast cancer treatment have yielded mixed
results, and prolactin aids breast cancer cells in resisting chemotherapy drugs, activating
pro-cancer pathways like “phosphoinositide-3-kinase” PI3/Akt, and bolstering cancer
cell survival. Oxytocin, known for its role in childbirth and
milk secretion, has been linked to cancer development, with elevated levels observed
in breast cancer patients. Oxytocin has the potential to boost the growth of breast
cancer cells while amplifying the effectiveness of tamoxifen, a drug used in breast
cancer treatment. Progesterone, intricately involved in breast cell division, exhibits
both proliferative and inhibitory effects on breast cancer cells, initially promoting
growth but later potentially slowing it down [53]. It can render breast cancer cells more responsive to growth signals, contributing
to tumor progression and increasing resistance to treatment. Progesterone receptors
(PR) serve as valuable biomarkers for studying estrogen receptor-alpha (ERα) function
and predicting breast cancer prognosis [54]. Finally, estrogen, crucial in estrogen receptor-positive breast cancer,
constitutes 70% of cases, and imbalanced estrogen metabolism can produce harmful molecules,
known as estrogen quinones, which can damage DNA and heighten breast cancer risk [55].
Varied factors favoring breast cancer protection through hormonal events
Various breastfeeding-related factors contribute significantly to breast cancer prevention
by influencing endocrine and hormonal regulation. These factors encompass:
Suckling stimulus
Suckling intensity, influenced by factors like frequency, bout duration, and daily
duration, correlates with the duration of postpartum amenorrhea [56]. During infant suckling, sensory receptors in the nipple send signals to the anterior
pituitary gland, triggering the release of prolactin and oxytocin. This process stimulates
the release of milk through a positive feedback loop. Prolactin, previously believed
to directly maintain amenorrhea, is currently regarded as an indicator of how often
the infant is nursing [57].
Role of growth factor β
If we consider the direct correlation between the cumulative number of ovulatory cycles
and the risk of breast cancer, the ovulatory suppression associated with prolonged
breastfeeding should contribute to a reduction in both factors [58]. Notably, an extended duration of breastfeeding consistently emerges as a robust
predictor of breast cancer risk across studies. Beyond temporary or long-term changes
in pituitary and ovarian hormones [59]
[60]
[61]
[62]. Noteworthy among these factors is transforming growth factor-beta, which exhibits
hormonally regulated negative effects on breast cancer cells [63]
[64]. The impact on the expression of these factors and their receptors assumes importance
due to their intricate connections with oncogenes, proto-oncogenes, and the expression
of tumor suppressors [65]. Specifically, there is compelling evidence suggesting that transforming growth
factor-beta (TGF-β), expressed during lactation, serves as a hormonally regulated
negative growth factor in human breast cancer cells. Behavioral and environmental
factors influencing the expression of these growth factors assume significance due
to their intricate connections with oncogenes, proto-oncogenes, and the expression
of tumor suppressors. Understanding the interplay between hormonal regulation, environmental
influences, and the expression of growth factors like TGF-β is essential for unraveling
the complex dynamics influencing breast cancer development [65].
Hormonal changes and their impact
The hormonal shifts associated with lactation, characterized by heightened prolactin
levels, and reduced estrogen production, may potentially hinder the initiation or
growth of breast tumors. Lactation is often accompanied by a reduction or cessation
of ovulation, which could contribute to additional protection against breast cancer.
The interplay between these hormonal changes during lactation appears to create an
environment that is less conducive to the development and progression of breast tumors
[60].
Longer lactational amenorrhea
Lactational amenorrhea, a natural contraceptive method, relies on breastfeeding patterns.
It postpones the resumption of regular ovarian cycles by interfering with the release
pattern of gonadotropin-releasing hormone (GnRH) from the hypothalamus and, consequently,
luteinizing hormone (LH) from the pituitary gland [11]. Although the follicle-stimulating hormone (FSH) levels remain sufficient for follicle
growth during lactation, the disrupted LH signaling diminishes estradiol production
by these follicles. This altered hormonal environment impedes the typical preovulatory
LH surge, leading to follicles that either fail to rupture or become atretic or cystic
[57]. In women, hyperprolactinemia often leads to amenorrhea, resembling the lactational
amenorrhea situation [66]
[67]. Suckling-induced prolactin release can directly suppress the menstrual cycle, affect
the ovary, or decrease GnRH release [57].
Age at menarche and menopause
The impact of reproductive factors contributing to breast cancer risk is crucial for
comprehensive risk assessment and preventive strategies. Although early onset of menstruation
and late cessation of menstruation are associated with modest increases in breast
cancer risk, the most consistently observed risk factor across diverse populations
is the age at which a woman undergoes her first full-term pregnancy. This pivotal
reproductive milestone emerges as a common denominator in breast cancer risk assessment,
emphasizing its significance in shaping preventive strategies across various demographic
contexts [68].
Estrogen window hypothesis
Proposed in 1980 by Korenman, the “estrogen window hypothesis” suggests that the most
favorable conditions for breast cancer induction result from unopposed estrogen stimulation,
while normal post ovulation progesterone secretion reduces susceptibility. The hypothesis
posits that the interplay of normal estrogen stimulation and luteal inadequacy, marked
by diminished progesterone secretion, can explain the main epidemiological features
of breast cancer. It underscores the notion that unopposed estrogen stimulation is
particularly conducive to tumor induction. Despite the initial assumption that progesterone
acts as an antiestrogen on breast epithelium akin to its impact on endometrial epithelium,
a comprehensive evaluation of epidemiologic and experimental evidence challenges this
premise. Contrary to expectations, the accumulated data indicates that a higher frequency
of ovulatory cycles, not a reduction, constitutes the primary determinant of breast
cancer risk. This
reframing emphasizes the complexity of hormonal dynamics influencing breast cancer
etiology and encourages ongoing exploration in this field [58].
Direct physical changes
The act of lactation has beneficial impact on the interaction between the mammary
epithelium and the stroma. Breast tissue could be particularly responsive to these
lactational changes during early reproductive life [69]
[70].
Cumulative lactation
The prolonged duration of breastfeeding stands out as the most robust predictor of
breast cancer risk. This is underscored by the fact that concentrations of toxic organochlorines
in human breast milk decrease as the cumulative duration of lactation increases [71]. The suppression of ovulation associated with prolonged breastfeeding should effectively
reduce both factors if connected to breast cancer risk [58]. This dual impact highlights the potential protective role of extended breastfeeding,
addressing not only the presence of harmful substances but also contributing to a
decreased risk of breast cancer. Consistent with reported duration effects, the elimination
of carcinogens through breast milk secretion aligns with observed trends. In humans,
there is an observable decrease in breast milk concentrations of toxic
organochlorines with increasing cumulative lactation. This correlation sheds light
on the potential protective mechanisms associated with extended breastfeeding, as
it not only nourishes infants but also serves as a means of reducing the presence
of harmful substances [72].
Molecular Mechanisms Underlying Protection
Molecular Mechanisms Underlying Protection
Cellular differentiation and maturation
Acknowledging the epidemiological, clinical, and experimental evidence that highlights
the crucial connection between ovarian function and the risk of breast cancer, it
becomes clear that factors such as early onset of menstruation, delayed menopause,
and parity play a significant role in influencing susceptibility [73]
[74]. [Fig. 3] shows molecular mechanisms of breastfeeding aiding in protection against breast
cancer.
Fig. 3
Molecular mechanisms of breastfeeding aiding in protection against breast cancer.
In the context of breast development, different stages of breast lobules become evident,
starting with the simple, undifferentiated lobules type 1 (Lob 1), and progressing
to the more complex lobules type 2 and lobules type 3 [75]
[76]. Pregnancy, along with lactation, emerge as hallmark episodes, driving the breast’s
most development marked by lobules type 4 [76]. However, post-menopause both nulliparous and parous women find common ground, characterized
by Lob 1 predominance. It is worth noting that the increased risk of breast cancer
in women who have never given birth (nulliparous) compared to those who have (parous),
even when their postmenopausal lobular compositions appear to be similar, suggests
the presence of subtle inherent differences or varying
susceptibility to carcinogenic factors within lobules type 1 [77]. A conjecture emerges positing that Lob 1 in nulliparous and certain parous women
remains in an undifferentiated state, housing epithelial cells predisposed to carcinogenic
triggers and consequent neoplastic transformation, denoted as Stem cells one. In contrast,
Lob 1 formations within early postmenopausal parous women, untouched by mammary pathology,
host transformation-resistant stem cells 2 [76]. Central to this notion is the hypothesis that early pregnancy-triggered differentiation
confers a distinct genomic signature upon stem cells two, diverging them onto a course
resilient against carcinogenic activation. While in-depth exploration is requisite
to decipher the intricate mechanisms and gene interplay shaping stem cells 2 exclusive
genomic landscape, the cumulative
available data indicate that the differentiation induced by pregnancy guides stem
cells 1’s transition into the steadfast stem cells 2, collectively endowing the mammary
gland with an inherent armor against malignant progression [76].
Throughout pregnancy and lactation, dynamic transformations transpire within the breast
tissue in anticipation of milk synthesis and nursing.
Apoptosis (programmed cell death)
Apoptosis, a fundamental process of controlled cell death, plays a crucial role in
various aspects of mammary development, ranging from the initial construction of the
mammary gland during early embryonic stages to the regression phase after the lactation
cycle. The highest frequency of apoptotic events occurs during mammary involution,
marked by a significant wave of programmed cell death [78]. During this period, most of the secretory epithelium in the lactating breast undergoes
apoptosis, as the mammary gland regresses and undergoes restructuring in anticipation
of the next lactation cycle [79]. An examination of morphological constituents and gene expressions intimates a two-phased
portrayal of involution-driven apoptosis: a preliminary controlled apoptosis prompted
by hormonal withdrawal, succeeded by a subsequent wide-ranging
apoptosis modulated by proteases. This later stage is triggered by changes in cell-matrix
interactions and detachment from anchoring. Intriguingly, breastfeeding emerges as
an activator of elevated apoptosis rates within breast tissue. This discernment implies
that cells marred by DNA damage or mutations are nudged towards apoptosis, curtailing
their malignant evolution. The regulation of apoptosis is a complex interplay orchestrated
by intricate signaling pathways intrinsically embedded within cells. The transformative
impact of breastfeeding encompasses hormonal and molecular signals, potentially amplifying
the activation of pro-apoptotic pathways. This mechanism, in turn, furnishes a strategic
avenue for the eradication of cells bearing incipient cancerous modifications.
Reduced ovulation frequency
Extensive investigations have substantiated a correlation between a woman’s susceptibility
to breast cancer and her interaction with hormones produced by her ovaries, specifically
the endogenous estrogen and progesterone. Reproductive factors that prolong the duration
and intensity of exposure to ovarian hormones, which in turn stimulate cellular proliferation,
have demonstrated associations with an increased risk of breast cancer [80]
[81]. Some scientific inferences suggest that these differentiated cells exhibit heightened
resilience against malignant transformation compared to their undifferentiated counterparts,
underpinning the notion that differentiation fosters resistance to cancer cell metamorphosis
[76]. Breastfeeding, particularly exclusive
breastfeeding, can initiate a process called lactational amenorrhea, where the cessation
of ovulation and menstruation results from hormonal shifts tied to lactation. This
occurrence is partially regulated by the hormone prolactin, which inhibits the release
of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Consequently, this
leads to a reduction in the secretion of luteinizing hormone (LH) and follicle-stimulating
hormone (FSH) from the pituitary gland [11]. These hormones are integral to fostering ovarian follicle maturation and triggering
ovulation. Reduced frequency of ovulation translates to a decrease in menstrual cycles
and diminished exposure to estrogen and progesterone—hormones that wield influence
over the progression of hormone-responsive breast cancers [82]
[83]. It is important to highlight that estrogen can stimulate the proliferation of breast
cells, which contributes to the development of breast cancer [84]. Through this transient attenuation of ovulation and curtailed hormonal exposure,
breastfeeding holds the promise of mitigating the risk linked to breast cancer engendered
by estrogen influence.
HAMLET
HAMLET, short for “Human a-lactalbumin made lethal to tumor cells”, represents an
exceptional protein-lipid complex distinguished by its remarkable capacity to selectively
target and eliminate tumor and immature cells, all the while preserving the healthy
and differentiated ones [85]
[86]. The complex structure results from the combination of partially unfolded alpha-lactalbumin
and oleic acid, both of which are common components found in human milk. This configuration
shift transpires upon calcium ion (Ca2+) removal from native a-lactalbumin, leading to protein unfolding that unveils fresh
fatty acid binding domains, securely accommodating oleic acid [87]
[88]. Critical to its
tumor-targeting potency, oleic acid is indispensable, as solely the unfolded protein
lacks the capacity to induce tumor cell death [89]
[90].
HAMLET a shield against tumorigenesis
HAMLET (Human a-lactalbumin made lethal to tumor cells), a unique complex formed from
alpha-lactalbumin and oleic acid present in human milk, has been shown to induce cell
death in both tumor and bacterial cells [91]. Tumor cells experience apoptosis triggered by HAMLET, while well-differentiated
normal cells exhibit resilience against its impact [92]. The widespread effectiveness of HAMLET in combating tumors is emphasized by its
ability to act against a wide range of tumor cells, including more than 40 different
types of lymphoma and in vitro carcinoma cell lines [90]. This breadth suggests the initiation of fundamental cell death pathways within
tumor cells [91]. Although the mechanism
leading to cell death is complex, thorough examination has outlined multiple pathways
through which HAMLET induces cell death in tumor cells, including apoptosis, anoikis,
and autophagy [91]
[93]. Following cellular internalization, HAMLET instigates swift mitochondrial obliteration
[93]. Nucleic acid traslocation exerts its impact by intricately binding to histones
and nucleosomes. It disrupt the functionality of transcription machinery. The discovery
of HAMLET’s activity was an unexpected outcome during research involving human milk
fractions aimed at studying bacterial adhesion to lung carcinoma cell lines. In addition
to its role in blocking adhesion, a specific milk fraction surprisingly revealed its
ability to trigger cell death, leading to apoptosis [93]. HAMLET possesses unique biological properties, selectively eliminating cancerous
cells through a mechanism resembling apoptosis, while leaving normal cells unharmed
[88]. This indicates that HAMLET manages to bypass the diverse mechanisms of resistance
to apoptosis that are often exhibited by tumor cells. Instead, it initiates alternative
cell death pathways that remain functional in these tumor cells. HAMLET highlights
the therapeutic possibilities within human milk, where a wealth of molecules may have
beneficial implications for various human health conditions. The conditions necessary
for HAMLET formation occur in the stomachs of breast-fed infants. The lower pH environment
in the stomach may induce protein unfolding through calcium release, while acid-sensitive
lipases catalyze the breakdown of milk triglycerides to release oleic
acid [94]. The potential consequences extend to lymphoid cells within the gut-associated lymphoid
tissue, as breast-fed infants demonstrate significantly lower rates of lymphoma compared
to bottle-fed infants. HAMLET’s broad anti-tumor effectiveness is evident in laboratory
studies, and its therapeutic capabilities are confirmed through in vivo experiments
using a rat model of human glioblastoma, as well as in patients with skin cancer (papillomas)
and bladder cancer [94]
[95].
In a previous investigation, the influence of HAMLET on mammary cells was examined
closely. HAMLET-embedded plastic pellets were administered to lactating mice and a
three-day exposure resulted in morphological changes characteristic of apoptosis.
There was also an increase in caspase-3 activity observed in alveolar epithelial cells
close to the HAMLET pellets, with no discernible effect in distant areas or in contralateral
glands. This effect was unique to HAMLET, as native α-lactalbumin or isolated fatty
acids showed no impact on mammary glands. Additionally, HAMLET induced cell death
in a mouse mammary epithelial cell line [96]. HAMLET is capable to induce apoptotic cell death in mammary gland tissue. Prototypic
strategies for prophylactic cancer vaccination have been established using various
mouse breast cancer models. Alpha-lactalbumin, a differentiation protein specific
to the breast and
prominently expressed in most human breast carcinomas and solely in lactating mammary
epithelial cells, were chosen as the autoantigen for vaccination. Developing immunity
against alpha-lactalbumin provides significant protection against spontaneous tumor
growth in transgenic breast cancer mouse models and transplanted 4T1 breast tumors
in BALB/c mice [96]. Since alpha-lactalbumin is expressed conditionally during lactation, vaccination-induced
protection occurs without noticeable inflammation in non-lactating breast tissue [96]. This highlights the potential safety and effectiveness of alpha-lactalbumin vaccination
in protecting against breast cancer development in premenopausal women during their
post-childbearing years, a period when lactation can be avoided, and the risk of breast
cancer is higher. An overview of breastfeeding
associated molecular mechanisms aiding in protection against breast cancer is given
in [Table 1].
Table 1
Overview of breastfeeding associated molecular mechanisms aiding in protection against
breast cancer.
|
Breastfeeding associated molecular mechanism
|
Role in preventing breast cancer risk
|
Sources
|
|
Differentiation and maturation
|
Throughout pregnancy, labor, and lactation, the mammary gland undergoes a dynamic
remodeling process orchestrated by the complex interplay of lactogenic hormones. This
intricate sequence involves the activation of mammary stem and progenitor cells, ultimately
leading to the differentiation and maturation of cells responsible for milk production.
Importantly, this maturation process during breastfeeding contributes to a reduction
in the likelihood of tumor development or the onset of breast cancer.
|
Ambrosone et al. 2020 [97]
Witkowska-Zimny et al. 2017 [98]
|
|
Apoptosis
|
The mammary gland microenvironment undergoes significant remodeling during lactation,
potentially influencing breast cancer susceptibility. Elevated calcium concentrations
in breast milk actively suppress cellular apoptosis and necrosis through disruption
of intercellular connections. Additionally, Secretory IgA (SIgA) and Lactalbumin Alpha
(LALBA) exhibit anti-tumorigenic properties by suppressing breast cancer cell growth
and promoting apoptosis. Collectively, these findings suggest that breastfeeding may
contribute to the elimination of premalignant and malignant cells, providing a possible
mechanism for its observed association with reduced breast cancer risk.
|
Karbasi et al. 2022 [99]
Honorio-França et al. 2016 [100]
|
|
Immune System
|
Prolonged breastfeeding (> 12 months) reduces IRIS (BRCA1 splice variant) expression
through VD/VDR/STAT3 signaling, promoting terminal differentiation and immune clearance
of these cells upon involution [101]. Extended lactation promotes terminal differentiation of mammary epithelial cells,
promoting their post-involution clearance. Conversely, insufficient breastfeeding
may leave IRIS-overexpressing progenitors susceptible to immune evasion and potential
tumorigenesis during involution. These findings suggest a potential link between breastfeeding
duration, IRIS regulation, and breast cancer risk.
|
Castillo et al. 2022 [102]
ElShamy et al. 2016 [49]
|
|
Reduced Ovulation
|
Breastfeeding extends the postpartum period of amenorrhea, primarily through prolactin-mediated
inhibition of GnRH. This delay in ovulation translates to reduced lifetime estrogen
exposure, a known risk factor for breast cancer [103].
|
Beaber et al. 2008 [104]
Chen et al. 2023 [105]
|
|
HAMLET
|
Alpha-lactalbumin, a prominent protein in human milk, undergoes a remarkable transformation
when encountering oleic acid. This interaction forms HAMLET (Human Alpha-lactalbumin
Made Lethal to Tumors), a complex with potent cytotoxic activity towards tumor cells.
The most intriguing aspect of HAMLET lies in its selectivity. Unlike conventional
chemotherapeutic agents, HAMLET preferentially induces apoptosis (programmed cell
death) in tumor cells while sparing normal, differentiated cells.
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do Carmo França-Botelho et al. 2012 [106]
Abraham et al. 2023 [107]
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Link between duration of breastfeeding and breast cancer
Long noncoding RNAs have regulatory roles in multiple processes, including cell differentiation,
proliferation, migration, and the cell cycle. A recent study identified upstream Eleanor
(u-Eleanor), a novel lncRNA with key functions in breast cancer [101]. The connection between hormone-dependent reproductive risk factors in breast neoplasms
and LncRNAs, u-Eleanor, and HOTAIR was discovered. Studies showed that women who had
not lactated in the past had a higher level of u-Eleanor expression compared to those
who had breastfed [108]. Furthermore, there was an observed increase in u-Eleanor expression as the duration
of lactation decreased. Similarly, another study revealed a higher level of u-Eleanorin
in women who breastfed for a shorter duration (one to six months) compared to those
who breastfed for a longer period (greater
than 24 months) [109]
[110]. Both exclusive breastfeeding for up to six months and continued breastfeeding accompanied
with solid meals, for up to two years, according to the WHO standards, confer great
short-term and long-term health benefits for both the child and mother alike [103]
[111]. It not only provides cognitive and immune development for the infant, but also
prevents the threat of childhood cancers, obesity, sudden infant death syndrome (SID)
and respiratory diseases [103]
[112]
[113]
[114]
[115]. The immediate, as well as long-term impacts of breastfeeding have significant importance
for women health, wellbeing, and survival [14]
[116]. Instant effects of breastfeeding show up soon after childbirth, in the form of
visceral fat loss and improved metabolic functions [117]
[118]. It also serves as a natural contraceptive through inhibited ovulations and ensures
uterine health through suckling stimulus derived uterine contractions during breastfeeding,
aiding in the removal of fetal components which may otherwise
lead to postpartum hemorrhage [119]
[120]. Lactation speeds up the reversal of pregnancy-induced metabolic changes and fat
accumulation, which would otherwise pose a risk of metabolic diseases, insulin resistance,
gestational diabetes, and hypertension [121]
[122].
On the other hand, long-term impact of breastfeeding includes prevention of hypertension,
osteoporosis, cerebrovascular incidence and cancers, particularly the BRCA1 mutation-associated
breast cancer [117]
[123]. Numerous studies have confirmed opposing effects of extended breastfeeding practices
upon the risk of endometrial, ovarian and breast carcinomas in women [112]
[124]. It has been shown that breastfeeding not only prevents the risk of breast cancer
development, but also its recurrence in breast cancer treated cases [125].
Lactation inhibition and hormone use
Hormones like estrogens have been commonly employed to hinder lactation. For instance,
in the study by Newcomb et al., 43% of women aged 20–74 years in the control group
reported using hormones to inhibit milk flow [126]. Given that diethylstilbestrol has been linked to a slight increase in breast cancer
risk among older women, various studies have explored whether the apparent protective
link between lactation and breast cancer risk might be influenced by an elevated risk
among users of lactation suppressants [70]. The suppressants utilized encompass a diverse group, including prolactin inhibitors,
androgens, vitamins, and estrogen. Consequently, it is likely that their effects,
if any, are also diverse. In general, no heightened risk of breast cancer has been
observed among women who reported using lactation suppressants [35]. In early reproductive life, direct physical changes accompanying milk production
in the breast may favorably influence breast tissue [60]
[61]. Lactation is believed to reduce the risk of breast cancer, potentially by interrupting
ovulation or modifying pituitary and ovarian hormone secretion [60]
[61]
[127]
[128]. The use of hormones for lactation suppression, including pills, injections, and
unknown forms, was associated with an exceedingly small and nonsignificant increase
in risk
among premenopausal women. Postmenopausal women, however, exhibited a slight increase
in risk with no discernible gradient of effect. Additionally, diethylstilbestrol use
during pregnancy has been linked to a modest increase in breast cancer risk among
older women [129]
[130]. This underscores the potential protective role of extended breastfeeding in mitigating
the impact of ovulation on breast cancer risk [58].
Future directions and multidisciplinary approaches
The future implications stemming from breast cancer and breastfeeding research are
both promising and diverse. They offer the potential for personalized risk evaluation,
precisely targeted therapies, and the identification of early detection markers grounded
in cellular differentiation and maturation mechanisms. A comprehensive understanding
of the pathways that lead to apoptosis induced by breastfeeding opens innovative avenues
for cancer treatment and the prevention of resistance mechanisms. Finally, the clinical
applications of HAMLET, including its role in cancer treatment and prevention, along
with the development of breast cancer vaccines that target specific proteins, provide
exciting prospects for improving breast cancer outcomes and advancing personalized
healthcare.
Conclusion
In this extensive examination of the intricate interplay between breast cancer and
breastfeeding, we have ventured into the complex molecular mechanisms that underlie
this vital connection. Breast cancer remains a significant global health challenge,
impacting women across diverse regions and communities. Despite advances in medical
practices, its incidence continues to climb, posing both public health dilemmas and
economic burdens. Reproductive factors, including breastfeeding practices, have emerged
as modifiable risk factors capable of exerting a profound influence on breast cancer
susceptibility. Beyond its primary role in infant nutrition, breastfeeding bestows
a plethora of benefits upon both mothers and infants. Notably, breastfeeding has demonstrated
to be effective in risk reduction of breast cancer, with each additional 12 months
of breastfeeding correlating with a substantial reduction in this risk. Our investigation
into the molecular aspects of this relationship
has unveiled critical pathways that breastfeeding confers to prevent breast cancer:
cellular differentiation and maturation, apoptosis (programmed cell death), reduced
ovulation frequency, and the intriguing Human a-lactalbumin made lethal to tumor cells
(HAMLET). The intricate molecular details emphasize the multifaceted aspect of breast
cancer, especially in its association with breast feeding. While breastfeeding undeniably
provides concrete protective advantages, the Health Organization (WHO) and UNICEF
aim to heighten awareness and bolster breastfeeding practices on a global scale. By
shedding light on the intricate molecular mechanisms through which breastfeeding mitigates
breast cancer risk, this review underscores the imperative of fostering increased
breastfeeding rates, both in low- and high-income countries. Such efforts promote
breastfeeding, which significantly reduces the risk of breast cancer. It is noteworthy
that global breastfeeding rates still fall below
recommended levels.
