Progesterone Signaling and Mammary Gland Morphogenesis

Progesterone was identified as a mammogenichormone several years ago but until now its precise rolein mammary development has remained obscure. Recentlywith the generation of several transgenic mouse models and development of reagents for analysisof progesterone receptor expression, the role ofprogesterone signaling in mammary development isbecoming more clear. The most significant observationsto emerge from these studies are (1) progesteronereceptors (PR)4 are present in a heterogeneous manner inthe epithelial cells and undetectable in the surroundingfat pad; (2) they are essential for lobuloalveolar and not for ductal morphogenesis; (3)progesterone signaling through progesterone receptors,leading to lobuloalveolar development, is initiated inthe epithelium and may occur through paracrinemechanisms; and (4) a regulated expression of the twoisoforms of progesterone receptor is critical formaintaining appropriate responsiveness to progesteroneand hence, epithelial cell replicative homeostasis.These studies also reveal that the consequences ofprogesterone signaling through progesterone receptor maydepend on the cell context, cell-cell andcell-extracellular matrix interactions, the dynamics ofPR turnover and the fate of PR positivecells.     

Mammary Gland Growth and Development from the Postnatal Period to Postmenopause: Ovarian Steroid Receptor Ontogeny and Regulation in the Mouse

Ovarian steroid hormones play a critical role inregulating mammary gland growth and development. Themammary gland sequentially acquires and cyclicallyexhibits proliferative responses to estrogen and/or progesterone from birth to postmenopause. Thefocus of this review is to presentour currentunderstanding of estrogen and progesterone receptordistribution in epithelial and stromal cells and theirfunctions in relation to mammary gland development.Insights gained from the study of the normal mammarygland are relevant to our understanding of theconditions which may predispose women to the developmentof breast cancer as well as to alterations inhormonal regulation that occur in breastcancer.     

Regulation of Mammary Gland Growth and Morphogenesis by the Mammary Fat Pad: A Species Comparison

The growth and morphogenesis of mammaryparenchyma varies substantially between species and isregulated by an array of systemic and local factors.Central to this regulation is the mammary fat pad, amatrix of adipose and connective tissue capable ofmediating hormone action and synthesizing an array ofgrowth regulatory molecules. In this article wehighlight differences between the morphologicaldevelopment of the mammary parenchyma in rodents, humans,and ruminant dairy animals, placing emphasis ondifferences in the cellular composition and structure ofthe mammary fat pad. While a great deal remains to be understood about the ability of stroma tolocally regulate mammary development, the significanceof its contribution is becoming increasingly apparent.The actions of several steroid and peptide hormones appear to be mediated by an array of growthfactors, proteases and extracellular matrix componentssynthesized by constituents of the mammary fat pad.Further, mammary adipose tissue represents a significant store of lipid which, by itself and through itsderivatives, could influence the growth of mammaryepithelium in diverse ways. This review describes theintegral role of the mammary fat pad duringmammogenesis, emphasizing the point that species differencesmust be addressed if local growth and morphogenicmechanisms within the mammary gland are to beresolved.     

Developmental and Hormonal Regulation of Protein N-Glycosylation in the Mammary Gland

Glycosylation represents the most commonconjugation of both membrane-bound and secreted proteinsof animal cells. Among the different types ofglycosylation, the N-linked attachment of sugars to thepolypeptide backbone is by far the most abundantmodification. The biosynthesis of the precursorcarbohydrate unit of these proteins is initiated by astepwise assembly ofGlc₃Man₉Glc₂NAc P-P-Dolin the dolichol cycle, its transfer en bloc to the nascent polypeptidein the rough endoplasmic reticulum (RER),³followed by excision of the glucosyl residues byprocessing-specific enzymes, glucosidase I and II, alsoresident in the endoplasmic reticulum. Additionalposttranslational modifications of the carbohydratemoiety in the RER, Golgi, and trans -Golgi network,differ for individual glycoproteins for the completionof final products as high mannose, complex orhybrid glycoproteins en route to their finaldestinations in the secretory pathway. The enzymeGlcNAc-1-P transferase (GPT) catalyzes the first andcommitted step, i.e., the transfer of GlcNAc-1-P fromUDP-GlcNAc to Dol-P to form GlcNAc-P-PDol, in theassembly of the oligosaccharide precursor. GlucosidaseI triggers the maturation phase by clipping the distal 1,2-linked Glc residue on the incipientglycoprotein. The critical juxtaposition of the twoenzymes in the multistep pathway makes them excellentcandidates for the overall regulation of proteinN-glycosylation. The highly elevated needs of glycosylationduring lactation demand regulation of glycosylation inthe gland over and above the levels in the quiescent,virgin and postlactating, regressed gland.     

The Role of Mammary Stroma in Modulating the Proliferative Response to Ovarian Hormones in the Normal Mammary Gland

Postnatal mammary gland development is highlydependent on the ovarian steroids, estrogen andprogesterone. However, evidence from both in vitro andin vivo studies indicates that steroid-induceddevelopment occurs indirectly, requiring stromalcooperation in epithelial proliferation andmorphogenesis. Stromal cells appear to influenceepithelial cell behavior by secretion of growth factorsand/or by altering the composition of the extracellular matrix inwhich epithelial cells reside. This review will discussthe requirement for stromal tissue in modulatingproliferative responses to ovarian hormones during postnatal development and the potential role ofthe EGF, IGF, HGF and FGF³ growth factorfamilies. Additionally, the roles of extracellularmatrix proteins, including fibronectin, collagens andlaminin, will be summarized.     

A Specific Role for Cyclin D1 in Mammary Gland Development

Cyclin D1 is a critical component of the core cell cycle machinery. Mice lacking cyclin D1 develop mammary glands that fail to undergo normal lobuloalveolar proliferation during pregnancy. Thus, cyclin D1 seems to play a critical role in pregnancy-induced proliferation of mammary epithelium. Cyclin D1 also participates in neoplasia, as the majority of human mammary carcinomas contain elevated levels of this cyclin.     

A Crucial Role for Fibroblast Growth Factor Signaling in Embryonic Mammary Gland Development

The fibroblast growth factors (Fgfs) represent a large group of intercellular signaling molecules that mediate their effects by binding to a class of cell surface enzymes belonging to the receptor tyrosine kinase family (FgfRs). In vitro, Fgf signaling can induce potent mitogenic, motogenic, and angiogenic cellular responses, and has been associated with a multitude of biological processes. The development of gene targeting and transgenic strategies has provided unequivocal evidence for the key involvement of Fgf signaling in mammalian developmental processes. In this review we highlight recent findings that demonstrate a critical requirement for Fgf signaling in the induction and development of the embryonic mammary gland. Furthermore, we briefly discuss the potential of Fgfs to act as oncogenic factors in mammary neoplasia.     

A Role for Fibroblast Growth Factor Signaling in the Lobuloalveolar Development of the Mammary Gland

The inappropriate expression of growth factors, or activating mutations of their receptors, have been implicated as causative factors in mouse and human mammary cancer. For example, it has been known for some time that three members of the fibroblast growth factor (FGF)³ family behave like oncogenes in virally induced mammary cancer of mice. In normal circumstances, signaling via FGF receptors is known to mediate growth, differentiation, and patterning, during embryogenesis and fetal development. A powerful approach to dissecting the roles for these signaling pathways is to determine the developmental consequences of abrogating their function in transgenic mice. In this review, we describe the use of dominant negative FGF receptors to evaluate the contribution of specific FGF signals in normal mammary gland development. These studies have revealed that normal lobuloalveolar development requires FGF signaling to the mammary epithelium, a function that is presumably usurped by MMTV in mouse mammary tumorigenesis.     

Borderline Developmental Dysplasia of the Hip: A Risk Factor Predicting the Development and Poor Prognosis after Core Decompression for Idiopathic Osteonecrosis of the Femoral Head

ObjectiveIt is unclear whether idiopathic osteonecrosis of the femoral head (ONFH) is associated with borderline developmental dysplasia of the hip (BDDH). This study aimed to compare the incidence of BDDH between patients with idiopathic ONFH and matched control subjects and determine the influence of BDDH on poor prognosis after core decompression (CD).MethodsWe retrospectively examined 78 consecutive patients (111 hips) with idiopathic ONFH undergoing CD and 1:2 matched with 156 control subjects (222 hips). The anteroposterior pelvic radiographs were used to measure the acetabular anatomical parameters and divide included subjects into BDDH or non‐BDDH group. The incidence of BDDH and acetabular anatomical parameters were compared between patients with idiopathic ONFH and matched controls. Clinical outcomes, such as Harris Hip Score (HHS), progression of collapse, and conversion to total hip arthroplasty (THA), were compared between patients with BDDH and without BDDH in the idiopathic ONFH group, with a mean follow‐up of 72.1 ± 36.6 months.ResultsPatients with idiopathic ONFH had a significantly higher incidence of BDDH than matched controls (29.7% vs 12.2%, p < 0.001). Less acetabular coverage was also found in patients with idiopathic ONFH than in matched controls as demonstrated by lower CEA (28.5° ± 4.7° vs 33.1° ± 5.7°, p < 0.001), AHI (82.4 ± 5.0 vs 86.3 ± 5.4, p < 0.001), ADR (299.6 ± 28.4 vs 318.8 ± 31.3, p < 0.001), and a higher sharp angle (40.0° ± 3.4° vs 37.4° ± 3.7°, p < 0.001). In patients with idiopathic ONFH, the BDDH group had a significantly lower mean HHS at the last follow‐up (83.5 ± 17.4 vs 91.6 ± 9.7, p = 0.015) with a different score distribution (p = 0.004), and a lower 5‐year survival rate with both clinical failure (66.7%, 95% CI 52.4%–84.9% vs 83.7%, 95% CI 75.2%–93.1%; p = 0.028) and conversion to THA (74.6%, 95% CI 60.7%–91.6% vs 92.1%, 95% CI 85.6%–99.0%; p = 0.008) as the endpoints than the non‐BDDH group.ConclusionThe incidence of BDDH was significantly higher in patients with idiopathic ONFH than matched controls, and idiopathic ONFH patients who underwent CD with BDDH had lower mean HHS as well as 5‐year survival rate than those without BDDH. Therefore, BDDH should be considered a risk factor predicting the development of idiopathic ONFH as well as poor prognosis after CD.