Theories for the origin of milk have been recorded since the time of Ancient Greeks. In those times it was believed that milk was derived from special vessels that connected the uterus to the breasts. The "chyle theory" on the origin of milk was another prominent theory which persisted well into the nineteenth century before the realisation that milk components were derived from blood and some milk constituents were actually synthesized within the breasts. The demonstration that milk ejection was the expulsion of milk that had already been secreted and that milk secretion was a separate continuous process, set the background for the development for the current understanding of milk synthesis and secretion. Today we know that there are two stages in the initiation of lactation- secretory differentiation and secretory activation. Secretory differentiation represents the stage of pregnancy when the mammary epithelial cells differentiate into lactocytes with the capacity to synthesize unique milk constituents such as lactose. This process requires the presence of a 'lactogenic hormone complex' of the reproductive hormones, estrogen, progesterone, prolactin and some metabolic hormones. Secretory activation on the other hand, is the initiation of copious milk secretion and is associated with major changes in the concentrations of many milk constituents. The withdrawal of progesterone triggers the onset of secretory activation but prolactin, insulin and cortisol must also be present. This review describes the works of pioneers that have led to our current understanding of the biochemical and endocrinological processes involved in the initiation of human lactation.
"In parallel to the morphogenic changes in the pregnant mammary gland, luminal epithelial cells undergo differentiation as many genes involved in milk synthesis begin to be expressed during midpregnancy (Anderson et al. 2007). With the withdrawal of progesterone at parturition, the gland undergoes secretory activation as the mammary gland is set up as an exocrine gland to perform its main function to produce, secrete, and deliver milk (Pang & Hartmann 2007). The gland functions to produce milk until weaning of the pups where the buildup of milk within alveoli acts as a trigger for the mammary gland to undergo involution. "
[Show abstract][Hide abstract] ABSTRACT: Gap junctions formed of connexin subunits link adjacent cells by direct intercellular communication that is essential for normal tissue homeostasis in the mammary gland. The mammary gland undergoes immense remodeling and requires exquisite regulation to control the proliferative, differentiating and cell death mechanisms regulating gland development and function. The generation of novel genetically-modified mice with reduced or ablated connexin function within the mammary gland has advanced our understanding of the role of gap junctions during the complex and dynamic process of mammary gland development. These studies have revealed an important stage specific role for Cx26 and Cx43, while Cx30 and Cx32 can be eliminated without compromising the gland. Yet, there remains gaps in our understanding of the role of mammary gland gap junctions.
"Oxytocin (OT) is a neuroendocrine hormone that is essential for normal breastfeeding physiology, as it stimulates breast myoepithelial cell contraction, which transfers milk to the areola for the infant (Pang and Hartmann, 2007). OT has been implicated in maternal behavior and in forming and maintaining social bonds, particularly in its interaction with dopamine (Pedersen et al., 1994; Pedersen, 1997; Numan et al., 2005; Aragona et al., 2006). "
"Levels of intracellular glucocorticoids, particularly cortisol, rise gradually during pregnancy [54-57], where the breast experiences extensive proliferation of the terminal ductal lobuloalveolar units (TDLUs) . At parturition, cortisol levels rise dramatically [54,57], and the breast undergoes functional differentiation of the TDLUs, marking the initiation of lactation . Liganded GR is known to support acinus formation and spatial organization during pregnancy and lactation by regulating the expression of proteins required for maintenance of tight junctional complexes, such as adherens junctions proteins ZO-1 and β-catenin [12,60,61]. "
[Show abstract][Hide abstract] ABSTRACT: While glucocorticoids and the liganded glucocorticoid receptor (GR) have a well-established role in the maintenance of differentiation and suppression of apoptosis in breast tissue, the involvement of unliganded GR in cellular processes is less clear. Our previous studies implicated unliganded GR as a positive regulator of the BRCA1 tumour suppressor gene in the absence of glucocorticoid hormone, which suggested it could play a similar role in the regulation of other genes.
An shRNA vector directed against GR was used to create mouse mammary cell lines with depleted endogenous levels of this receptor in order to further characterize the role of GR in breast cells. An expression microarray screen for targets of unliganded GR was performed using our GR-depleted cell lines maintained in the absence of glucocorticoids. Candidate genes positively regulated by unliganded GR were identified, classified by Gene Ontology and Ingenuity Pathway Analysis, and validated using quantitative real-time reverse transcriptase PCR. Chromatin immunoprecipitation and dual luciferase expression assays were conducted to further investigate the mechanism through which unliganded GR regulates these genes.
Expression microarray analysis revealed 260 targets negatively regulated and 343 targets positively regulated by unliganded GR. A number of the positively regulated targets were involved in pro-apoptotic networks, possibly opposing the activity of liganded GR targets. Validation and further analysis of five candidates from the microarray indicated that two of these, Hsd11b1 and Ch25h, were regulated by unliganded GR in a manner similar to Brca1 during glucocorticoid treatment. Furthermore, GR was shown to interact directly with and upregulate the Ch25h promoter in the absence, but not the presence, of hydrocortisone (HC), confirming our previously described model of gene regulation by unliganded GR.
This work presents the first identification of targets of unliganded GR. We propose that the balance between targets of liganded and unliganded GR signaling is responsible for controlling differentiation and apoptosis, respectively, and suggest that gene regulation by unliganded GR may represent a mechanism for reducing the risk of breast tumourigenesis by the elimination of abnormal cells.
BMC Cancer 04/2014; 14(1):275. DOI:10.1186/1471-2407-14-275 · 3.36 Impact Factor
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