Women diagnosed with breast cancer within 5 to 10 years of childbirth have significantly increased risk for metastatic recurrence [97,98]. It has been proposed that the higher probability of developing a metastatic disease during that period would be caused by mammary gland involution. During this process, which starts when milk production ends, either after birth in the absence of nursing or after weaning, dramatic tissue remodeling occurs in the mammary gland of all female mammals [99,100].

In female mice, expression of IL-6, LIF and OSM is low during lactation, but increases during involution together with the activation of Stat3 in mammary tissue. It has been shown that LIF is the cytokine responsible for activation of this transcription factor [101,102], while IL-6 induced ERK1/2 MAPK phosphorylation, which also plays a significant role during mammary regression [103]. Furthermore, OSM and OSMR are upregulated in response to STAT3 activation and the signaling triggered by this cytokine promoted the expression of metalloproteinases MMP3, MMP12, and MMP14, that are relevant for remodeling normal mammary tissue, but would also facilitate mammary tumor invasiveness [104].

Transgenic mice with mammary specific expression of the protease pappalysin-1 (PAPP-A), which is extensively overexpressed in breast cancers [105], have shown that extended lactation is protective against the oncogenic effect of PAPP-A, while abrupt halt of nursing increased its tumorigenic impact [106]. Interestingly, during mammary involution, PAPP-A expression is induced by IL-6 among other cytokines, and sudden interruption of lactation have triggered an increase in inflammation markers [107]. Therefore, possibly by ameliorating inflammation in the post-partum mammary microenvironment, extended lactation may be protective against breast cancer via suppression of PAPP-A [108].

Mastitis, an inflammation of the mammary gland, is a worrying condition for nursing women, which may or may not be accompanied by infection. It is characterized by breast pain, swelling as well as redness, and can be followed by serious complications such as abscess and septicemia. Studies in different western countries revealed a relevant impact of this pathology with incidences of about 10–20% during the first 3 months post-delivery [109]. This pathology has also a great impact on cow milk production, since it causes premature weaning leading to reduced milk yield and quality. In addition, mastitis increases the cost of cattle management together with danger of antibiotic residues in commercialized milk [110]. This is due to the fact that in dairy cows, mastitis is usually caused by different bacteria including Gram-positive, e.g., Staphylococcus aureus (S. aureus) and Gram-negative, such as Escherichia coli (E. coli) [111]. The pathogenesis caused by E. coli and other Gram-negative bacteria is often characterized by an acute inflammation, which, however, may eventually lead to pathogen clearance [112]. On the other hand, Staphylococci are the bacteria most commonly isolated from cases of subclinical mastitis [113]. Infection with these Gram-positive pathogens often causes mild signs of mastitis, but ineffective pathogen clearance frequently leads to chronic infection [114]. Importantly, infections by S. aureus are also a serious problem for women, because antibiotic resistance may cause eventual severity and difficulties to cure the illness [115].

Analysis of the transcriptome of primary bovine mammary epithelial cells after challenging them with heat-inactivated preparations of E. coli or S. aureus showed that the first rapidly and strongly induced expression of cytokines and chemokines while S. aureus elicited a retarded response. The genes that were most strongly upregulated by E. coli were clustered into a regulatory network with tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) in a central position. In contrast, the S. aureus response induced a functional network dominated by IL-6, although this cytokine would be also relevant for E. coli late response. Therefore, detection of IL-6 in milk has been proposed as a predictor marker for subclinical mastitis [116].

Interestingly, not only IL-6—but also its receptor, IL-6R—has been reported to be upregulated in the mammary glands of mastitic cows. This enhanced expression has been attributed to increased DNA methylation level during inflammation. Specifically, it has been proposed that the DNA methylation level in exon 2 of IL-6R could also be a potential biomarker for monitoring bovine mastitis [117]. Furthermore, Zhu et al., demonstrated an increase in the IL-6 mRNA in infected mammary lobes, but not in the mammary lobes that did not develop mastitis [118]. Similarly, comparing protein content in breast milk from human nipple single pores revealed that milk from mastitic lobes contained higher concentration of IL-6 than milk from healthy glands [119].

Plasma cell mastitis (PCM), also known as mammary ductal ectasia, is a special form of mastitis that typically occurs in young and middle-aged women at nonpregnant or non-nursing stages. IL-6/STAT3 signaling is activated in PCM and may play an important role in the pathogenesis of this illness [120]. Associated with this discovery, it has been proposed that sinomenine hydrochloride may achieve a therapeutic effect on PCM based on its anti-inflammatory and immunoregulatory properties, which are exerted by IL-6/JAK2/STAT3 pathway downregulation [121].