**Author details**

immune responses [51–54]. Interestingly, after weaning, mammary epithelial cells themselves express transcripts traditionally associated with immune cells [55, 56] and acquire phagocytic capability [57]. Therefore, it has not been possible to completely determine which cell types and in what part are responsible for the observed immune-like gene signatures. Particularly, there is not much data about the participation of adaptive immune cells, but innate immune cell populations have been partially characterized. Specifically, it has been observed that granulocyte infiltration in the mouse gland on the first day of involution suggest the involvement of this cell type in early involution [58]. In addition, resident macrophages seem to be required for this phase, while infiltrating macrophages are important during the remodeling stage [52]. It was observed that on this last phase, macrophages express low iNOS, high arginase-1, and the mannose receptor, which is consistent with alternative activation or M2 polarization of these cells [59]. Importantly, this phenotype correlated with breast tumor promotion in patients [60] and murine mammary

The earlier mentioned STAT3 and NF-κB signaling pathways, as well as others involving transforming growth factor beta (TGF-β) and the retinoid acid receptors (RARs)/retinoid X receptors (RXRs), participate in mammary gland involution as well as in breast cancer development. After weaning, target genes of RARα/p300 and RelA/p65, which belong to the NF-κB protein family, are induced, and high activity of the proteins coded by these genes, e.g., *MMP9*, *Capn1*, and *Capn2*, has been detected in breast cancer cells. Calpains belong to a family of calcium-dependent intracellular cysteine proteases involved in a wide variety of physiological and pathological processes. These proteases are heterodimers, consisting of a small regulatory subunit, encoded by CAPN4 gene, common for both members, and a large catalytic subunit encoded by either CAPN1 or CAPN2. During mammary gland involution and cancer progression, these proteins are relevant for modifying the extracellular matrix, allowing tissue remodeling and/or cell invasion. In addition, calpains also cleave intracellular proteins located in the cell membrane, lysosomes, mitochondria, and nuclei, favoring cell death during involution and cell anchoring loss during tumor

As in other physiological processes, the use of conditional knockout mice and the application of high-throughput techniques have been very useful to understand that normal postlactation mammary gland involution relays on the fine-tune coordination of multiple signaling pathways. Although involution is a physiologically normal, developmentally orchestrated tissue-remodeling process, it shares striking similarities with pathologically induced wound-healing and tumor-promotional microenvironments. This highlights the relevance of further investigating this process, since it may yield novel therapeutic targets or prognostic markers for breast cancer. Importantly, studying this particular phase of mammary gland biology may help us to pinpoint subtle changes in a pro-oncogenic

tumor progression [61].

48 Current Topics in Lactation

progression [62].

**6. Conclusion**

Edith C. Kordon1 \* and Omar A. Coso<sup>2</sup>

\*Address all correspondence to: ekordon@gmail.com

1 Department of Biological Chemistry, Institute of Physiology, Molecular Biology and Neuroscience (IFIBYNE-UBA-CONICET), School of Exact and Natural Sciences, University of Buenos Aires, (FCEN-UBA), Ciudad Universitaria, Buenos Aires, Argentina

2 Department of Physiology, Molecular and Cellular Biology, Institute of Physiology, Molecular Biology and Neuroscience (IFIBYNE-UBA-CONICET), School of Exact and Natural Sciences, University of Buenos Aires (FCEN-UBA), Ciudad Universitaria, Buenos Aires, Argentina
