OXTR overexpression leads to abnormal mammary gland development in mice

Abstract

Oxytocin receptor (OXTR) is a G-protein coupled receptor and known for regulation of maternal and social behaviors. Null mutation (Oxtr-/-) leads to defects in lactation due to impaired milk ejection and maternal nurturing. Overexpression of OXTR has never been studied. To define the functions of OXTR overexpression, a transgenic mouse model that overexpresses mouse Oxtr under β-actin promoter was developed (++Oxtr). ++Oxtr mice displayed advanced development and maturation of mammary gland, including ductal distention, enhanced secretory differentiation and early milk production at non-pregnancy and early pregnancy. However, ++Oxtr dams failed to produce adequate amount of milk and led to lethality of newborns due to early involution of mammary gland in lactation. Mammary gland transplantation results indicated the abnormal mammary gland development was mainly from hormonal changes in ++Oxtr mice but not from OXTR overexpression in mammary gland. Elevated OXTR expression increased prolactin-induced phosphorylation and nuclear localization of STAT5 (p-STAT5), decreased progesterone level, leading to early milk production in non-pregnant and early pregnant females, whereas low prolactin and STAT5 activation in lactation led to insufficient milk production. Progesterone treatment reversed the OXTR-induced accelerated mammary gland development by inhibition of prolactin/p-STAT5 pathway. Prolactin administration rescued lactation deficiency through STAT5 activation. Progesterone plays a negative role in OXTR regulated prolactin/p-STAT5 pathways. The study provides evidence that OXTR overexpression induces abnormal mammary gland development through progesterone and prolactin-regulated p-STAT5 pathway.

Regulation of the JAK2-STAT5 Pathway by Signaling Molecules in the Mammary Gland

“…Overexpression of OXTR in the mouse mammary gland increases phosphorylation of STAT5 and induces lactation during the early lactation period, whereas OXTR-induced phosphorylation of STAT5 is decreased with attenuated milk production during the peak lactation period (Li et al, 2018). Furthermore, knockout of OXTR can impair milk ejection (Li et al, 2018). This finding indicates that the effect of the G αq signaling pathway in the mammary gland may be dependent on different lactation periods.…”

“…The oxytocin receptor (OXTR) is a G protein-coupled receptor that binds to G αq . Overexpression of OXTR in the mouse mammary gland increases phosphorylation of STAT5 and induces lactation during the early lactation period, whereas OXTR-induced phosphorylation of STAT5 is decreased with attenuated milk production during the peak lactation period (Li et al, 2018). Furthermore, knockout of OXTR can impair milk ejection (Li et al, 2018).…”

A battery-free, chipless, soft nanofluidic intracellular delivery patch for internal organs

“…The distance between the mammary surface contacted with the NanoFLUID and the inside mammary acini and ducts was measured to be between 100-300 μm 33,34 , indicating that the depth of NanoFLUID-mediated transfection could reach at least 100 μm in vivo.…”

The molecular consequences of androgen activity in the human breast

“…Particularly, basal cell expression of the lactation-associated genes ACTA2 and OXTR as well as TP63 were all reduced at the RNA and protein level suggesting contractile impairment (Fig. 3E, S8D) [46][47][48] . OXTR was also found reduced in epithelial enriched cis-male breast GTEx samples suggesting these changes result from androgen signaling (Fig.…”