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.	do Carmo França-Botelho et al. 2012 106 Abraham et al. 2023 107