Immune Cell Contribution to Mammary Gland Development

Abstract

Postpartum breast cancer (PPBC) is a unique subset of breast cancer, accounting for nearly half of the women diagnosed during their postpartum years. Mammary gland involution is widely regarded as being a key orchestrator in the initiation and progression of PPBC due to its unique wound-healing inflammatory signature. Here, we provide dialogue suggestive that lactation may also facilitate neoplastic development as a result of sterile inflammation. Immune cells are involved in all stages of postnatal mammary development. It has been proposed that the functions of these immune cells are partially directed by mammary epithelial cells (MECs) and the cytokines they produce. This suggests that a more niche area of exploration aimed at assessing activation of innate immune pathways within MECs could provide insight into immune cell contributions to the developing mammary gland. Immune cell contribution to pubertal development and mammary gland involution has been extensively studied; however, investigations into pregnancy and lactation remain limited. During pregnancy, the mammary gland undergoes dramatic expansion to prepare for lactation. As a result, MECs are susceptible to replicative stress. During lactation, mitochondria are pushed to capacity to fulfill the high energetic demands of producing milk. This replicative and metabolic stress, if unresolved, can elicit activation of innate immune pathways within differentiating MECs. In this review, we broadly discuss postnatal mammary development and current knowledge of immune cell contribution to each developmental stage, while also emphasizing a more unique area of study that will be beneficial in the discovery of novel therapeutic biomarkers of PPBC.

Keywords: Adaptive immunity; Inflammation; Innate immunity; Lactation; Mammary gland development; Postpartum breast cancer; Pregnancy.

Fig. 1

Lactation Challenges Mitochondrial Homeostasis. The lactating mammary gland challenges mitochondrial homeostasis via necessitating maintenance of a substantially demanding differentiated state. The mitochondria are under immense metabolic stress due to increased energetic demands as mammary epithelial cells work to produce milk. This stress results in augmented production of harmful reactive oxygen species (ROS) that result in mitochondrial damage/dysfunction. Under conditions of stress or damage, the mitochondria releases its components into the intracellular space to serve as damage associated molecular patterns (DAMPs). Aberrant mitochondrial components have been shown to elicit activation of innate immune modulators such as Toll-like receptors (TLRs), the inflammasome and the cGAS-STING pathway, all of which result in an inflammatory response. Ultimately, activation of innate immunity in response to mitochondrial damage promotes an environment of sterile inflammation; thus, innate immune activation during lactation is of interest for future studies