# Estrogen Signaling During Abrupt Involution and Long-Term Metabolic Signature Similar to Estrogen Receptor-Negative Breast Cancer

## TL;DR

Breast cancer risk may be linked to abrupt involution, which alters metabolism and estrogen signaling in ways similar to estrogen receptor-negative breast cancer.

## Contribution

The study reveals long-term metabolic changes in abrupt involution resembling estrogen receptor-negative breast cancer.

## Key findings

- Day 28 abrupt involution glands showed increased estrogen signaling and glucose metabolism compared to gradual involution.
- Day 120 abrupt involution glands exhibited metabolic features similar to estrogen receptor-negative breast cancer.
- Tamoxifen treatment in abrupt involution mice reversed some metabolic differences toward those seen in gradual involution.

## Abstract

Epidemiological data link a lack of breastfeeding with an increased risk of breast cancer. Breast tissue remodels after pregnancy through involution. Long-term breastfeeding results in gradual involution (GI), and a lack of breastfeeding leads to abrupt involution (AI). AI causes increased mammary gland estrogen signaling, causing adipocyte redifferentiation through neutrophil infiltration. Adipocyte differences and metabolic implications of involution have not been explored between AI and GI. As breast cancer is characterized as highly metabolic, we explored how adipocyte differences and metabolism during involution may support breast cancer risk. FVB/n was randomized to AI/GI and standardized to 6 pups on day 0/birth. AI mice had pups removed on day 7. GI mice had 3 pups removed on days 28 and 31. Mammary glands were harvested at 28, 56, and 120 days. A subset of AI mice were given tamoxifen for 21 days. Day 28 AI glands had upregulation of estrogen signaling, neutrophil degranulation, and glucose metabolism and downregulation of adipogenesis and glycolysis compared to Day 56 GI. Day 120 AI glands had downregulation of oxidative phosphorylation and upregulation of mitochondrial dysfunction similar to estrogen receptor-negative (ER−) pregnancy-associated breast cancer (PABC). AI with tamoxifen resulted in a similar metabolic phenotype to GI. Early metabolic phenotypes in AI and GI glands may be related to estrogen signaling. AI long-term transcriptional metabolic effects were similar to breast cancer.