Nuclear targeting of stanniocalcin to mammary gland alveolar cells during pregnancy and lactation

Abstract

Nuclear targeting of stanniocalcin to mammary gland alveolar cells during pregnancy and lactation. Am J Physiol Endocrinol Metab 289: E634 -E642, 2005; doi:10.1152/ajpendo.00098.2005.-In most mammalian tissues, the stanniocalcin-1 gene (STC-1) produces a 50-kDa polypeptide hormone known as STC50. Within the ovaries, however, the STC-1 gene generates three higher-molecular-mass variants known as big STC. Big STC is targeted locally to corpus luteal cells to block progesterone release. During pregnancy and lactation, however, ovarian big STC production increases markedly, and the hormone is released into the serum. During lactation, this increase in hormone production is dependent on a suckling stimulus, suggesting that ovarian big STC may have regulatory effects on the lactating mammary gland. In this report, we have addressed this possibility. Our results revealed that virgin mammary tissue contained large numbers of membrane-and mitochondrial-associated STC receptors. However, as pregnancy progressed into lactation, there was a decline in receptor densities on both organelles and a corresponding rise in nuclear receptor density, most of which were on milk-producing, alveolar cells. This was accompanied by nuclear sequestration of the ligand. Sequestered STC resolved as one ϳ135-kDa band in the native state and therefore had the appearance of a big STC variant. However, chemical reduction collapsed this one band into six closely spaced, lower-molecular-mass species (28 -41 kDa). Mammary gland STC production also underwent a dramatic shift during pregnancy and lactation. High levels of STC gene expression were observed in mammary tissue from virgin and pregnant rats. However, gene expression then fell to nearly undetectable levels during lactation, coinciding with the rise in nuclear targeting. These findings have thus shown that the mammary glands are indeed targeted by STC, even in the virgin state. They have further shown that there are marked changes in this targeting pathway during pregnancy and lactation, accompanied by a switch in ligand source (endogenous to exogenous). They also represent the first example of nuclear targeting by STC.

Passive immunization of lactating mice with stanniocalcin-1 antiserum reduces mammary gland development, milk fat content, and postnatal pup growth

“…To observe any effects of passive immunization on STC-1 receptor levels, the paired thoracic mammary glands in each group were pooled (n ϭ 5) and subjected to Dounce homogenization to isolate the nuclear, mitochondrial, and microsomal membrane fractions. Receptor-binding studies were then carried out on each fraction to obtain estimates of Kd and Bmax, as previously described (16). Values obtained were analyzed statistically with an unpaired two-tailed Student's t-test.…”

“…However, there were also significantly more triglycerides in the feces of antibodytreated pups, indicative of intestinal malabsorption. Milk contains measurable amounts of STC-1, as revealed by RIA (8) and immunocytochemistry, most of which is likely serum derived, as STC-1 gene expression is all but undetectable in the lactating mammary gland (16). Its presence in milk may therefore be indicative of an endocrine-exocrine pathway that governs fat absorption by the neonate gut.…”

“…This notion has recently been given credence in studies on virgin, pregnant, and lactating rats (16). The virgin rat mammary gland has high levels of STC-1 receptors and also expresses the STC-1 gene.…”

“…Mammary gland STC-1 expression also drops off and is no longer evident during lactation. Over the same time frame, receptors appear de novo on the nuclei of milk-producing alveolar cells, reaching peak levels during the lactation phase, and there is nuclear sequestration of the STC-1 ligand (16). As this all occurs at a time when the mammary glands have ceased making STC-1, the ligand must be systemically derived.…”

Apoptosis and Clearance of the Secretory Mammary Epithelium

“…Interestingly, PMCA2 expression is also regulated by enforced shape changes in mammary epithelial cells [13]. Stanniocalcin-1 (STC-1), a newly discovered mammalian hormone that accumulates nearly 3-fold upon milk stasis [14], has recently been implicated as an inducer of post-lactational involution [15].…”