Altered levels of cyclic nucleotides, cyclic AMP phosphodiesterase and adenylyl cyclase activities in normal, dysplastic and neoplastic human mammary tissue

Küng, Willy; Bechtel, Elke; Geyer, E.; Salokangas, Anneli; Preisz, J; Huber, Peter; Torhorst, J.; Jungmann, Richard A.; Talmadge, Kenneth W.; Eppenberger, Urs

doi:10.1016/0014-5793(77)80895-8

Cited by 26 publications

(8 citation statements)

References 8 publications

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“…Consistent with this observation, colorectal cancer cells generally have decreased basal levels of cGMP signaling and are hypersensitive to cGMP signaling activation with GC-C ligands compared to the normal colonic mucosa [78,80,82]. Mammary tumors have also been found to possess altered cyclic nucleotide signaling, particularly in terms of hydrolytic capacity [62,63,67,83,84,85]. For example, faster growing and more invasive mammary tumors show an overall decreased ability to hydrolyze cyclic nucleotides [62,63,67].…”

Section: Cyclic Nucleotide Signaling In Cancermentioning

confidence: 90%

The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

Fajardo

Piazza

Tinsley

2014

Cancers

189

169

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For more than four decades, the cyclic nucleotides cyclic AMP (cAMP) and cyclic GMP (cGMP) have been recognized as important signaling molecules within cells. Under normal physiological conditions, cyclic nucleotides regulate a myriad of biological processes such as cell growth and adhesion, energy homeostasis, neuronal signaling, and muscle relaxation. In addition, altered cyclic nucleotide signaling has been observed in a number of pathophysiological conditions, including cancer. While the distinct molecular alterations responsible for these effects vary depending on the specific cancer type, several studies have demonstrated that activation of cyclic nucleotide signaling through one of three mechanisms—induction of cyclic nucleotide synthesis, inhibition of cyclic nucleotide degradation, or activation of cyclic nucleotide receptors—is sufficient to inhibit proliferation and activate apoptosis in many types of cancer cells. These findings suggest that targeting cyclic nucleotide signaling can provide a strategy for the discovery of novel agents for the prevention and/or treatment of selected cancers.

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Section: Cyclic Nucleotide Signaling In Cancermentioning

confidence: 90%

The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

Fajardo

Piazza

Tinsley

2014

Cancers

189

169

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“…It has been known for many years that intracellular cAMP levels increase markedly in the mammary gland during pregnancy in the mouse (58), rat (60,61), and guinea pig (41) and are persistently elevated in rat and human mammary tumors (12,27,34,37,51), as is PKA activity (21,25,43,65). It is also now appreciated that cAMP-binding proteins-especially the RI␣ regulatory subunit of PKA (type I)-are overexpressed in a significant proportion of primary human breast tumors and that this feature has independent diagnostic and prognostic significance, being correlated with poor clinicopathology and outcome (49,50).…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Functional Interaction between Cyclin D1 and the Estrogen Receptor

Lamb

Ladha

McMahon

et al. 2000

Molecular and Cellular Biology

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We report that the functional interaction between cyclin D1 and the estrogen receptor (ER) is regulated by a signal transduction pathway involving the second messenger, cyclic AMP (cAMP). The cell-permeable cAMP analogue 8-bromo-cAMP caused a concentration-dependent enhancement of cyclin D1-ER complex formation, as judged both by coimmunoprecipitation and mammalian two-hybrid analysis. This effect was paralleled by increases in ligand-independent ER-mediated transcription from an estrogen response element containing reporter construct. These effects of 8-bromo-cAMP were antagonized by a specific protein kinase A (PKA) inhibitor, indicating that the signaling pathway involved was PKA dependent. Further, we show that culture of MCF-7 cells on a cellular substratum of murine preadipocytes also enhanced the functional interaction between cyclin D1 and ER in a PKA-dependent manner. These findings demonstrate a collaboration between cAMP signaling and cyclin D1 in the ligand-independent activation of ER-mediated transcription in mammary epithelial cells and show that the functional associations of cyclin D1 are regulated as a function of cellular context. Cyclin D1 is well recognized as a critical mitogen-regulated cell cycle control element which, in association with a catalytic subunit, cyclin-dependent kinase 4 (cdk4) or cdk6, effects the initial inactivating phosphorylation of the retinoblastoma protein, pRb, and thereby promotes proliferation (67, 78). Consistent with this biochemical function, cyclin D1 is demonstrably oncogenic in a variety of tissues (28).The cyclin D1 gene is amplified in approximately 30% of human breast adenocarcinomas, and the protein is reportedly overexpressed in 60 to 80% of all cases (5,8,13,23,24,48,55,79). Paradoxically, these tumors are characterized by low proliferation indices (55) and are thereby discriminated from cancers of this tissue associated with pRb inactivation (35). Indeed, there is no apparent relationship between cdk4 activity and cyclin D1 expression in breast cancer cell lines (75). Consistent with these findings, there has been one report that ectopic expression of cyclin D1 in mammary carcinoma cell lines can actually inhibit proliferation (29). Taken together, these observations suggest that cyclin D1 possesses functions independent of, or in addition to, participation in pRb-mediated promotion of cell cycle progression during mammary carcinogenesis.Cyclin D1 also plays a specific and indispensable part in normal mammary gland biology. Mice nullizygous for the cyclin D1 gene exhibit, among surprisingly few defects, a dramatic impairment of lobuloalveologenesis associated with pregnancy (68). Further, in vitro models of this developmental process reveal a marked induction of cyclin D1 in the absence of corresponding increases in associated kinase activity toward the formation of milk-secreting structures (52). Thus, cyclin D1 appears to possess an exceptional function in the mammary epithelium, involved in both the normal development and malignant transformation o...

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“…In situ, cAMP levels increase as the mammary gland grows during pregnancy (9,10), and they are elevated in several breast carcinomas (11,12). To obtain more direct evidence as to whether cAMP may function as an intracellular mediator of hormone or growth factor action in the mammary gland, we investigated the effects of raising cAMP levels in small regions of the mouse mammary gland by using slow-release plastic implants.…”

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confidence: 99%

“…Numbers of glands treated are shown in parentheses; error bars represent 95% confidence intervals. The following criteria were used to score glands: 0, ductal tips are same diameter as subtending ducts, which are spindly; +1, some but not all duct tips are enlarged, no end buds, ductal diameter is unaffected; +2, small end buds are present, enlarged tips, ductal diameter is increased; +3, larger end buds are present but they are few in number (<10), ductal diameter is increased; +4, numerous end buds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) are present but some tips remain unstimulated, ductal diameter is comparable with that of hormonally intact animal; +5, entire gland appears stimulated, many end buds (>20) are present; +6, as in +5 but the gland is intensely stimulated in places with "grape cluster" outgrowths on some ducts.…”

mentioning

confidence: 99%

In vivo, cAMP stimulates growth and morphogenesis of mouse mammary ducts.

Silberstein¹,

Strickland²,

Trumpbour³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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In culture, cAMP is known to be mitogenic for mammary cells and several other epithelia, but evidence for a similar role in vivo has been only correlative. We have used plastic implants to cause slow release of cholera toxin and other cAMP-active agents to local areas of mammary glands in ovariectomized mice. Elevated levels of intracellular cAMP around the implants promoted vigorous growth and normal ductal morphogenesis, while distant sites were unaffected. Local effects of cAMP included restoration of normal ductal caliber, formation of new end buds, and reinitiation of DNA synthesis in both epithelium and surrounding stroma. Thus, cAMP is both a mitogenic and a morphogenetic factor in this tissue.Numerous in vitro studies have shown cAMP to be growth promoting for mouse, rat, and human mammary epithelia (1-4) and for a variety of other epithelial cell types (5-8). In situ, cAMP levels increase as the mammary gland grows during pregnancy (9, 10), and they are elevated in several breast carcinomas (11,12). To obtain more direct evidence as to whether cAMP may function as an intracellular mediator of hormone or growth factor action in the mammary gland, we investigated the effects of raising cAMP levels in small regions of the mouse mammary gland by using slow-release plastic implants.End buds, the primary sites of mammary epithelial proliferation in subadult virgin mice, are complex highly mitotic structures comprised of the stem cell progenitors of myoepithelial and ductal cells (13). As the growth points for the ductal tree, end buds are the focus of mammary growth regulatory influences during this stage in development of the gland (14). We here present evidence that, in situ, local elevation of cAMP stimulated formation of new end buds in regressed ducts, apparently replacing the normal hormonal requirements for this type of development. CT Dosage. Commercial CT contains 4.8% by weight of toxin protein, the bulk of the preparation being NaCl and Tris HCl (55% and 37.6%, respectively). The most commonly used implant was prepared with 1 mg of the commercial preparation dissolved in 0.25 ml of Elvax. The dried Elvax pellet weighed -40 mg and contained 48 ,ug of toxin protein or 1.2 ,ug in an implant-sized piece weighing 1 mg. The useful dose range for this implant type is 0.1-1.2 ,ug of toxin. MATERIALS AND METHODSRelease of CT from Elvax. The release kinetics of CT was studied in vitro. Pellets prepared with either 1 mg or 10 mg of the toxin were cut into implant-sized pieces, weighed, and sealed in nylon bags (Nitex), which were then placed in 1.5 ml of normal saline at 37°C on a rotator (1 rpm). At 24-hr intervals, the bags were removed and the saline was assayed for protein against a CT standard using the Bradford method (16). Bags were then rinsed and replaced in fresh saline. An adequate amount of Elvax with toxin was available for three trials, one of which is shown here (Fig. 5); the release profile was the same for all three trials. Surgical Implantation. The abdominal skin of Nembutalanesthet...

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Altered levels of cyclic nucleotides, cyclic AMP phosphodiesterase and adenylyl cyclase activities in normal, dysplastic and neoplastic human mammary tissue

Cited by 26 publications

References 8 publications

The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

Regulation of the Functional Interaction between Cyclin D1 and the Estrogen Receptor

In vivo, cAMP stimulates growth and morphogenesis of mouse mammary ducts.

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