Characterization of weaning-induced breast involution in women: implications for young women’s breast cancer

Abstract

In rodents, weaning-induced mammary gland involution supports increased mammary tumor incidence, growth, and progression to metastasis. Further, the protumor attributes of gland involution are COX-2 dependent and mitigated by short-duration non-steroidal anti-inflammatory drugs (NSAIDs), suggesting a potential prevention strategy. However, the transition from lactation to postweaning breast involution has not been rigorously evaluated in healthy women. Here we queried breast biopsies from healthy women (n = 112) obtained at nulliparity, lactation, and multiple postweaning time points using quantitative immunohistochemistry. We found that mammary remodeling programs observed in rodents are mirrored in the human breast. Specifically, lactation associates with the expansion of large, secretory mammary lobules and weaning associates with lobule loss concurrent with epithelial cell death and stromal hallmarks of wound healing, including COX-2 upregulation. Altogether, our data demonstrate that weaning-induced breast involution occurs rapidly, concurrent with protumor-like attributes, and is a potential target for NSAID-based breast cancer prevention.

Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes

“…We analyzed this publicly available data set to focus on gene sets from healthy nulliparous and postpartum subjects within 2 years of their last childbirth. As anticipated from previous reports 56,57 , we observed some normal involution signatures in the postpartum normal tissue expression data sets, such as a parity signature (Supplementary Fig. 1a) and the immune infiltrate signature (Supplementary Fig.…”

Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis

“…Stained sections were scanned using the Aperio AT2 slide scanner (Leica Biosystems, Wetzlar, Germany). Signal quantification was performed by Aperio ImageScope v12.1.0.5029 as described previously [ 79 ]. For quantitation, all mice and tumors found in the stained tissue section were included for every analysis, unless staining was unsuccessful as defined as loss of tissue from slide and/or failure for positive controls to stain.…”

S-nitrosylated and non-nitrosylated COX2 have differential expression and distinct subcellular localization in normal and breast cancer tissue

“…Previous studies show that COX2 is dynamically regulated in mammary gland tissue across a menstrual cycle, and induced by ovarian hormones in rodents 31 , 50 . In support of menopausal status impacting COX2 expression in human breast tissue, a study of breast biopsies from healthy women showed that COX2 expression is dynamically regulated across a reproductive cycle 53 . Further, previously published studies revealed that COX2 expression in healthy, premenopausal women was highly variable, with positive CX229 or CX294 staining ranging from undetectable to high 31 , 42 , 54 .…”