Deletion of Stat3 Blocks Mammary Gland Involution and Extends Functional Competence of the Secretory Epithelium in the Absence of Lactogenic Stimuli

TLDR

Stat3, a cytokine‑activated transcription factor, is essential for mammary gland involution, with its activity rising sharply after weaning and its loss delaying this process in mice. The study aimed to create a more complete Stat3 knockout by deleting exons 15–21 in mammary epithelium. This was achieved by generating mice with a targeted deletion of Stat3 exons 15–21 specifically in mammary epithelial cells. The resulting Stat3‑null mice exhibited no detectable Stat3 protein, normal pregnancy‑driven development and lactation, but delayed involution with preserved epithelial function up to 6 days post‑weaning, correlating with impaired proteinase activity and demonstrating that mammary tissue can maintain function without lactogenic signals.

Abstract

The transcription factor Stat3 is activated through tyrosine phosphorylation by many cytokines and is a fundamental mediator of their signals. In the mammary gland, Stat3 activity increases sharply shortly after weaning, and involution is delayed in mice, that contain a mutant Stat3 lacking 33 amino acids including the key tyrosine residue. We have now generated a more extensive mutation of Stat3 through the deletion of exons 15–21 in mammary epithelium. This resulted in the loss of 245 amino acids including the DNA binding and SH2 domains, and Stat3 protein was undetectable. Pregnancy-mediated mammary development and lactation were normal in these mice. Involution was delayed and, remarkably, Stat3-null mammary epithelium maintained its functional integrity and competence even 6 d after weaning, whereas control mammary tissue was rendered nonfunctional within 2 d. The lack of remodeling and functional stasis of the epithelium correlated with the disruption of proteinase activity. Our data demonstrate that mammary tissue can retain its functional competence in the absence of external lactogenic stimuli and demonstrate a delay in the initiation of the irreversible stage of involution.