Abrupt involution induces inflammation, estrogenic signaling, and hyperplasia linking lack of breastfeeding with increased risk of breast cancer. Breast Cancer Res 2019 Jul 17;21(1):80
Date
07/19/2019Pubmed ID
31315645Pubmed Central ID
PMC6637535DOI
10.1186/s13058-019-1163-7Scopus ID
2-s2.0-85070057466 (requires institutional sign-in at Scopus site) 29 CitationsAbstract
BACKGROUND: A large collaborative analysis of data from 47 epidemiological studies concluded that longer duration of breastfeeding reduces the risk of developing breast cancer. Despite the strong epidemiological evidence, the molecular mechanisms linking prolonged breastfeeding to decreased risk of breast cancer remain poorly understood.
METHODS: We modeled two types of breastfeeding behaviors in wild type FVB/N mice: (1) normal or gradual involution of breast tissue following prolonged breastfeeding and (2) forced or abrupt involution following short-term breastfeeding. To accomplish this, pups were gradually weaned between 28 and 31 days (gradual involution) or abruptly at 7 days postpartum (abrupt involution). Mammary glands were examined for histological changes, proliferation, and inflammatory markers by immunohistochemistry. Fluorescence-activated cell sorting was used to quantify mammary epithelial subpopulations. Gene set enrichment analysis was used to analyze gene expression data from mouse mammary luminal progenitor cells. Similar analysis was done using gene expression data generated from human breast samples obtained from parous women enrolled on a tissue collection study, OSU-2011C0094, and were undergoing reduction mammoplasty without history of breast cancer.
RESULTS: Mammary glands from mice that underwent abrupt involution exhibited denser stroma, altered collagen composition, higher inflammation and proliferation, increased estrogen receptor α and progesterone receptor expression compared to those that underwent gradual involution. Importantly, when aged to 4 months postpartum, mice that were in the abrupt involution cohort developed ductal hyperplasia and squamous metaplasia. Abrupt involution also resulted in a significant expansion of the luminal progenitor cell compartment associated with enrichment of Notch and estrogen signaling pathway genes. Breast tissues obtained from healthy women who breastfed for < 6 months vs ≥ 6 months showed significant enrichment of Notch signaling pathway genes, along with a trend for enrichment for luminal progenitor gene signature similar to what is observed in BRCA1 mutation carriers and basal-like breast tumors.
CONCLUSIONS: We report here for the first time that forced or abrupt involution of the mammary glands following pregnancy and lack of breastfeeding results in expansion of luminal progenitor cells, higher inflammation, proliferation, and ductal hyperplasia, a known risk factor for developing breast cancer.
Author List
Basree MM, Shinde N, Koivisto C, Cuitino M, Kladney R, Zhang J, Stephens J, Palettas M, Zhang A, Kim HK, Acero-Bedoya S, Trimboli A, Stover DG, Ludwig T, Ganju R, Weng D, Shields P, Freudenheim J, Leone GW, Sizemore GM, Majumder S, Ramaswamy BAuthors
Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of WisconsinAnthony J. Trimboli PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBiopsy
Breast Feeding
Breast Neoplasms
Collagen
Disease Models, Animal
Disease Susceptibility
Epithelial Cells
Estrogens
Female
Flow Cytometry
Gene Expression Profiling
Humans
Hyperplasia
Immunohistochemistry
Inflammation
Lactation
Mice
Pregnancy
Receptors, Estrogen
Risk Assessment
Risk Factors
Signal Transduction
Steroids
