Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium

Abstract

Functional development of mammary epithelium during pregnancy depends on prolactin signaling. However, the underlying molecular and cellular events are not fully understood. We examined the specific contributions of the prolactin receptor (PrlR) and the signal transducers and activators of transcription 5a and 5b (referred to as Stat5) in the formation and differentiation of mammary alveolar epithelium. PrlR- and Stat5-null mammary epithelia were transplanted into wild-type hosts, and pregnancy-mediated development was investigated at a histological and molecular level. Stat5-null mammary epithelium developed ducts but failed to form alveoli, and no milk protein gene expression was observed. In contrast, PrlR-null epithelium formed alveoli-like structures with small open lumina. Electron microscopy revealed undifferentiated features of organelles and a perturbation of cell–cell contacts in PrlR- and Stat5-null epithelia. Expression of NKCC1, an Na-K-Cl cotransporter characteristic for ductal epithelia, and ZO-1, a protein associated with tight junction, were maintained in the alveoli-like structures of PrlR- and Stat5-null epithelia. In contrast, the Na-Pi cotransporter Npt2b, and the gap junction component connexin 32, usually expressed in secretory epithelia, were undetectable in PrlR- and Stat5-null mice. These data demonstrate that signaling via the PrlR and Stat5 is critical for the proliferation and differentiation of mammary alveoli during pregnancy.

Essential Role for Zinc Transporter 2 (ZnT2)-mediated Zinc Transport in Mammary Gland Development and Function during Lactation

“…In stark contrast, the MECS of ZnT2-null mice were severely disorganized, lacking a distinct cell-cell junctions and presented with numerous pseudolumina (Fig. 8B), similar to the morphology seen in Stat5-null mice with impaired MEC differentiation (45). Most notable were the disturbed apical membrane (Fig.…”

EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

“…Reports from hepatocytes and hepatocyte-related models have suggested that STAT proteins, including Stat5, are involved in functions associated with a high degree of cell differentiation (Runge et al, 1998;Wang et al, 1999), in analogy with the role of Stat5 in mammary gland development and lactogenesis (Miyoshi et al, 2001).…”

Transcription factor regulatory networks in mammary epithelial development and tumorigenesis

“…STAT5A has a critical role in the establishment of luminal alveolar progenitor cells Previous work from Hennighausen group had demonstrated that targeted disruption of STAT5A resulted in impaired alveolar differentiation during pregnancy and a failure to lactate (Liu et al, 1997;Miyoshi et al, 2001). To better understand the nature of this developmental block, a conditional STAT5A/5B allele was generated to permit mammary gland-specific ablation of both these key transcription factors following mammary epithelial expression of Cre recombinase (Yamaji et al, 2009).…”