Socs2 and Elf5 Mediate Prolactin-Induced Mammary Gland Development

Abstract

The proliferative phase of mammary alveolar morphogenesis is initiated during early pregnancy by rising levels of serum prolactin and progesterone, establishing a program of gene expression that is ultimately responsible for the development of the lobuloalveoli and the onset of lactation. To explore this largely unknown genetic program, we constructed transcript profiles derived from transplanted mammary glands formed by recombination of prolactin receptor (Prlr) knockout or wild-type mammary epithelium with wild-type mammary stroma. Comparison with profiles derived from prolactin-treated Scp2 mammary epithelial cells produced a small set of commonly prolactin-regulated genes that included the negative regulator of cytokine signaling, Socs2 (suppressor of cytokine signaling 2), and the ets transcription factor, E74-like factor 5 (Elf5). Homozygous null mutation of Socs2 rescued the failure of lactation and reduction of mammary signal transducer and activator of transcription 5 phosphorylation that characterizes Prlr heterozygous mice, demonstrating that mammary Socs2 is a key regulator of the prolactin-signaling pathway. Reexpression of Elf5 in Prlr nullizygous mammary epithelium restored lobuloalveolar development and milk production, demonstrating that Elf5 is a transcription factor capable of substituting for prolactin signaling. Thus, Socs2 and Elf5 are key members of the set of prolactin-regulated genes that mediate prolactin-driven mammary development.

Socs 3 modulates the activity of the transcription factor Stat3 in mammary tissue and controls alveolar homeostasis

“…Evidence is mounting that members of the SOCS family are essential in controlling the onset, extent, and duration of cytokine-induced Stat3 and Stat5 signaling. While Socs1 (Lindeman et al, 2001) and Socs2 (Harris et al, 2006) modulate prolactin signaling during pregnancy, Socs3 is essential for the functional development of mammary tissue during pregnancy and for the timely execution of mammary tissue remodeling during involution, as shown in this study.…”

“…In mammary tissue, Socs1 negatively regulates prolactin signaling and deletion of the respective gene results in precocious mammary development and a rescue of prolactin receptor (PrlR) haploinsuffiency (Lindeman et al, 2001). The inability of PrlR-hemizygous mice to form a functional alveolar compartment and lactate was also rescued by the deletion of both Socs2 alleles (Harris et al, 2006). In both instances, this functional rescue was paralleled by the activation of Stat5.…”

“…On the other hand, targeted over-expression of Socs1 in the late pregnant and lactating mouse mammary gland appeared to have no adverse effect (Petridou et al, 2003). Moreover, Socs2 was identified in a microarray screen as a prolactin-responsive gene and expression was detected in the epithelial compartment throughout pregnancy (Harris et al, 2006). These studies demonstrate that both Socs1 and Socs2 function as negative regulators of prolactin signaling.…”

Knocking Off SOCS Genes in the Mammary Gland

“…In a parallel study, an increase in Socs2 transcripts was observed in SCp2 mammary epithelial cells treated with a lactogenic stimulus. 18 Within the mammary gland, we have demonstrated that Socs2 has an important role in regulating PRL signal transduction during pregnancy and lactation. Although Socs2 was not essential for mammopoiesis and lactogenesis, removal of both Socs2 alleles in mice was sufficient to restore lactation in PRLR heterozygous females.…”

“…Transcript profiling studies to determine gene signatures associated with alveolar proliferation and differentiation have identified Socs2 as a PRL target gene. 18 In this study, transcript profiling was performed on outgrowths from day 6 and 8 pregnant recipients; these outgrowths were derived from explants of PRLR -/-or PRLR +/+ mammary epithelium grown in de-epithelialised fat-pads of wild-type mice. Socs2 was one of 239 epithelial-specific transcripts found to be down-regulated in the PRLR -/-transplants.…”