https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

The various contributions to this book record the remarkable progress that has been made in the understanding and management of pancreatic diseases over the last decade. The improvement in understanding has led in some cases to better management with improved outcome for the patient, whereas in other areas the way is now clear towards a better prospect for the future.

Progress and Prospects

The contribution of prolactin (PRL) to the pathogenesis and progression of human breast cancer at the cellular, transgenic, and epidemiological levels is increasingly appreciated. Acting at the endocrine and autocrine/paracrine levels, PRL functions to stimulate the growth and motility of human breast cancer cells. The actions of this ligand are mediated by at least six recognized PRL receptor isoforms found on, or secreted by, human breast epithelium. The PRL/PRL receptor complex associates with and activates several signaling networks that are shared with other members of the cytokine receptor superfamily. Coupled with the recently identified intranuclear function of PRL, these networks are integrated into the in vitro and in vivo actions induced by ligand. These findings indicate that antagonists of PRL/PRL receptor interaction or PRL receptor-associated signal transduction may be of considerable utility in the treatment of human breast cancer.

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The Role of Prolactin in Mammary Carcinoma

Prolactin (PRL) is a 23-kDa protein hormone that binds to a single-span membrane receptor, a member of the cytokine receptor superfamily, and exerts its action via several interacting signaling pathways. PRL is a multifunctional hormone that affects multiple reproductive and metabolic functions and is also involved in tumorigenicity. In addition to being a classical pituitary hormone, PRL in humans is produced by many tissues throughout the body where it acts as a cytokine. The objective of this review is to compare and contrast multiple aspects of PRL, from structure to regulation, and from physiology to pathology in rats, mice, and humans. At each juncture, questions are raised whether, or to what extent, data from rodents are relevant to PRL homeostasis in humans. Most current knowledge on PRL has been obtained from studies with rats and, more recently, from the use of transgenic mice. Although this information is indispensable for understanding PRL in human health and disease, there is sufficient disparity in the control of the production, distribution, and physiological functions of PRL among these species to warrant careful and judicial extrapolation to humans.

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What can we learn from rodents about prolactin in humans

The environment that the cumulus oocyte complex (COC) is exposed to during either in vivo or in vitro maturation (IVM) can have profound effects on the success of fertilisation and subsequent embryo development. Glucose is a pivotal metabolite for the COC and is metabolised by glycolysis, the pentose phosphate pathway (PPP), the hexosamine biosynthesis pathway (HBP) and the polyol pathway. Over the course of oocyte maturation, a large proportion of total glucose is metabolised via the glycolytic pathway to provide substrates such as pyruvate for energy production. Glucose is also the substrate for many cellular functions during oocyte maturation, including regulation of nuclear maturation and redox state via the PPP and for the synthesis of substrates of extracellular matrices (cumulus expansion) and O-linked glycosylation (cell signalling) via the HBP. However, the oocyte is susceptible to glucose concentration-dependent perturbations in nuclear and cytoplasmic maturation, leading to poor embryonic development post-fertilisation. For example, glucose concentrations either too high or too low result in precocious resumption of nuclear maturation. This review will discuss the relevant pathways of glucose metabolism by COCs during in vivo maturation and IVM, including the relative contribution of the somatic and gamete compartments of the COC to glucose metabolism. The consequences of exposing COCs to abnormal glucose concentrations will also be examined, either during IVM or by altered maternal environments, such as during hyperglycaemia induced by diabetes and obesity.

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The pivotal role of glucose metabolism in determining oocyte developmental competence

The role of prolactin in human breast cancer has been controversial. However, it is now apparent that human mammary epithelial cells can synthesize prolactin endogenously, permitting autocrine/paracrine actions within the mammary gland that are independent of pituitary prolactin. To model this local mammary production of prolactin (PRL), we have generated mice that overexpress prolactin within mammary epithelial cells under the control of a hormonally nonresponsive promoter, neu-related lipocalin (NRL). In each of the two examined NRL-PRL transgenic mouse lineages, female virgin mice display mammary developmental abnormalities, mammary intraepithelial neoplasias, and invasive neoplasms. Prolactin increases proliferation in morphologically normal alveoli and ducts, as well as in lesions. The tumors are of varied histotype, but papillary adenocarcinomas and adenosquamous neoplasms predominate. Neoplasms can be separated into two populations: one is estrogen receptor alpha (ERα) positive (greater than 15% of the cells stain for ERα), and the other is ERα− (<3%). ERα expression does not correlate with tumor histotype, or proliferative or apoptotic indices. These studies provide a mouse model of hormonally dependent breast cancer, and, perhaps most strikingly, a model in which some neoplasms retain ERα, as occurs in the human disease.

Prolactin induces ERα-positive and ERα-negative mammary cancer in transgenic mice

Development of in vitro matured/in vitro fertilized bovine embryos into morulae and blastocysts in defined culture media

Energy substrates and amino acids were evaluated for supporting acquisition of developmental competence by bovine cumulus-oocyte complexes during in vitro maturation. The basic culture medium (Basic Medium-3) used for in vitro maturation of oocytes was modified to produce six media containing glucose or glutamine with lactate or pyruvate, or glucose + glutamine, or glucose + 11 amino acids; a seventh (control) medium was TCM199. All media contained polyvinyl alcohol, gonadotropins, epidermal growth factor and oestradiol. Following maturation, oocytes were incubated in medium TALP for fertilisation, then cumulus cells were removed and presumptive embryos cultured for 48 h in a chemically defined medium (HECM-6) followed by 120 h in medium TCM199 + bovine calf serum. Six substrate treatments yielded similar first cleavage responses (66-78%) at 72 h post-insemination; however, blastocyst development at 192 h varied significantly. Oocytes matured in medium with glucose + 11 amino acids gave the best blastocyst development: 21% of inseminated oocytes or 25% of 2-cell embryos. Cumulus expansion in HECM-6 required glucose with either glutamine, 11 amino acids or lactate, or glutamine + lactate. We conclude that (1) the type of energy substrate or nutrient supplied during in vitro maturation of oocytes profoundly affects subsequent developmental competence; (2) oocyte maturation in simple medium containing glucose with lactate or 11 amino acids or glutamine, or lactate + glutamine, can support development equally as well as the complex medium, TCM199; and (3) media supporting at least moderate cumulus expansion during oocyte maturation also support subsequent blastocyst development.

Energy substrates and amino acids provided during in vitro maturation of bovine oocytes alter acquisition of developmental competence.

Four hypotheses were tested using isolated bovine oocytes. (1) Cumulus oocyte complexes (COCs) or denuded oocytes (DOs) were cultured with the protein kinase A (PKA) inhibitor, H-89, to test if meiotic arrest induced by forskolin or IBMX was due to cAMP-stimulated PKA activity or nonspecific effects of these cAMP elevators. (2) COCs were cultured with a protein kinase C (PKC) stimulator (PDD beta) or inhibitor (GF109203x) to test if PKC modulation altered oocyte maturation. (3) COCs were prestimulated for 15 min with (a) PDD beta followed by cotreatment with forskolin, or (b) with H-89 or H-7 followed by cotreatment with GF109203x, to test for interaction between the PKA and PKC signal transduction pathways. (4) H-89 was added to spontaneously maturing COCs at intervals of 0-18 hr to test if H-89 interfered with the transition between meiosis I and II. The results were as follows: H-89 interfered with forskolin or IBMX arrested oocytes in dose-response manner (IBMX ED50 = 41 microM for COCs; forskolin ED50 = 9 microM for denuded oocytes). Prestimulation with PKC induced meiotic resumption in COCs in spite of the presence of forskolin [PDD beta followed by PDD beta + forskolin: 41-47% germinal vesicle (GV) oocytes; forskolin alone: 90-95% GV], while PKC inhibition induced meiotic arrest to a similar extent as forskolin (GF109203x, 85% GV; forskolin, 67-80% GV). Additionally, pretreatment of COCs with H-89 interfered with GF109203x induced arrest (41% vs. 90% GV, respectively). Finally, H-89 interfered with the timely progression of COCs from meiosis I and II. These results indicate that the PKA and PKC pathways can modulate the maturation of bovine oocytes in vitro.

Roles of protein kinase A and C in spontaneous maturation and in forskolin or 3-isobutyl-1-methylxanthine maintained meiotic arrest of bovine oocytes.

The growth factor transforming growth factor alpha (TGFα) and the nuclear transcription factor c-myc often are overexpressed by human breast cancer cells. To produce models of breast disease with these etiologies, mice were generated that carried TGF-α- or c-myc-encoding transgenes. Transgene targeting employed the whey acidic protein (WAP) gene promoter, which is expressed in pregnant and lactating mammary epithelial cells. Non-virgin WAP-TGFα transgenic mice displayed accelerated mammary development during pregnancy, delayed post-parturient mammary involution, a progressive increase in the number of hyperplastic alveolar nodules (HANs), and development of mammary carcinoma with a mean latency of 9 months. Non-virgin WAP-c-myc transgenic mice displayed accelerated mammary gland development during pregnancy and development of mammary carcinomas with a latency of 8 months. Bitransgenic mice carrying both WAP-TGFα and WAP-c-myc displayed a dramatic acceleration of tumor development. These models identify the overexpression of TGFα or c-myc as etiological factors in the development of mammary neoplasia and demonstrate the increased severity of disease when both molecular alterations are present in the same cell.

Teresa A. Rose-Hellekant

Papers

Prolactin induces ERα-positive and ERα-negative mammary cancer in transgenic mice

Development of in vitro matured/in vitro fertilized bovine embryos into morulae and blastocysts in defined culture media

Energy substrates and amino acids provided during in vitro maturation of bovine oocytes alter acquisition of developmental competence.

Roles of protein kinase A and C in spontaneous maturation and in forskolin or 3-isobutyl-1-methylxanthine maintained meiotic arrest of bovine oocytes.

Transforming growth factor alpha- and c-myc-induced mammary carcinogenesis in transgenic mice.