cholecystokinin and Breast-Neoplasms

The leptin-signaling pathway and other genes involved in energy homeostasis (EH) have been examined in relation to breast cancer risk as well as to obesity. We test the hypothesis that genetic variation in EH genes influences survival after diagnosis with breast cancer and that body mass index (BMI) will modify that risk.. We evaluated associations between 10 EH genes and survival among 1,186 non-Hispanic white and 1,155 Hispanic/Native American women diagnosed with breast cancer. Percent Native American (NA) ancestry was determined from 104 ancestry-informative markers. Adaptive rank truncation product (ARTP) was used to determine gene and pathway significance.. The overall EH pathway was marginally significant for all-cause mortality among women with low NA ancestry (P(ARTP) = 0.057). Within the pathway, ghrelin(GHRL) and leptin receptor (LEPR) were significantly associated with all-cause mortality (P(ARTP) = 0.035 and 0.007, respectively). The EH pathway was significantly associated with breast cancer-specific mortality among women with low NA ancestry (P(ARTP) = 0.038). Three genes cholecystokinin (CCK), GHRL, and LEPR were significantly associated with breast cancer-specific mortality among women with low NA ancestry (P(ARTP) = 0.046,0.015, and 0.046, respectively), while neuropeptide Y (NPY) was significantly associated with breast cancer-specific mortality among women with higher NA ancestry(P(ARTP) = 0.038). BMI did not modify these associations.. Our data support our hypothesis that certain EH genes influence survival after diagnosis with breast cancer; associations appear to be most important among women with low NA ancestry.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Case-Control Studies; Cholecystokinin; Energy Metabolism; Female; Genetic Predisposition to Disease; Genotype; Hispanic or Latino; Homeostasis; Humans; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Receptors, Ghrelin; Receptors, Leptin; Risk Factors; Signal Transduction; White People; Young Adult

Cholecystokinin (CCK)-A and CCK-B/gastrin receptors were evaluated with in vitro receptor autoradiography in 406 human tumors of various origins using a sulfated 125I-labeled CCK decapeptide analogue 125I-(D-Tyr-Gly, Nle28,3l)-CCK 26-33 and 125I-labeled Leu15-gastrin as radioligands. CCK-B/gastrin receptors were found frequently in medullary thyroid carcinomas (92%), in small cell lung cancers (57%), in astrocytomas (65%), and in stromal ovarian cancers (100%). They were found occasionally in gastroenteropancreatic tumors, breast, endometrial, and ovarian adenocarcinomas. They were either not expressed or rarely expressed in colorectal cancers, differentiated thyroid cancers, non-small cell lung cancers, meningiomas, neuroblastomas, schwannomas, glioblastomas, lymphomas, renal cell cancers, prostate carcinomas, and the remaining neuroendocrine tumors (i.e., pituitary adenomas, pheochromocytomas, paragangliomas, and parathyroid adenomas). CCK-A receptors were expressed rarely in tumors except in gastroenteropancreatic tumors (38%), meningiomas (30%), and some neuroblastomas (19%). The identified CCK-A and CCK-B receptors were specific and of high affinity in the subnanomolar range. The rank order of potency of various CCK analogues was: sulfated CCK-8 = L-364,718 >> nonsulfated CCK-8 = L-365,260 > or = gastrin for CCK-A receptors and sulfated CCK-8 > gastrin = nonsulfated CCK-8 > L-365,260 > L-364,718 for CCK-B receptors. CCK-B receptors could also be selectively and specifically labeled with a newly designed nonsulfated 125I-(D-Tyr-Gly, Nle28,31)-CCK 26-33. Gastrin mRNA measured by in situ hybridization was present in most CCK-B receptor-positive small cell lung cancers, breast tumors, and ovarian tumors, representing the molecular basis of a possible autocrine growth regulation of these tumors. Gastrin and CCK mRNAs were lacking in medullary thyroid cancers. Thus, these results may have pathogenic, diagnostic, differential diagnostic, and therapeutic implications.

Topics: Autoradiography; Breast Neoplasms; Carcinoma, Small Cell; Cholecystokinin; Female; Gastrins; Humans; Lung Neoplasms; Neoplasms; Neuroendocrine Tumors; Ovarian Neoplasms; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Thyroid Neoplasms

We report the identification and characterization of the cis-acting elements responsible for the expression of the rat cholecystokinin (CCK) gene. Deletion mutations were constructed by linking variable amounts of the 5'-flanking region of the CCK gene to the bacterial chloramphenicol acetyltransferase reporter gene. The transcriptional activity of the CCK promoter deletion constructs was measured by monitoring chloramphenicol acetyltransferase enzyme activity after transient transfections. It is shown that sequences within 102 base pairs of the cap site are required for the expression from this promoter. This region contains a sequence that is identical to the -296 element of the human c-fos gene and is homologous with the polyoma enhancer and the cAMP- and 12-O-tetradecanoylphorbol-13-acetate-responsive elements described for several genes. In addition, the -119 to -81 fragment of the CCK promoter contains a transcriptional enhancer that potentiates the transcription from the herpes simplex virus thymidine kinase promoter in a position- and orientation-independent manner. DNase I protection and gel retardation experiments indicated the ability of several trans-acting factors found in nuclear extracts to bind specifically to regions of the CCK promoter. In particular, two complexes formed adjacent to the CCK enhancer region. One complex, CCK-1a, formed with sequences 5' to the enhancer whereas the other complex, CCK-1b, formed with the sequences identified by DNase I footprinting, 3' to the enhancer. Oligonucleotide competition experiments indicated that these complexes are formed by the same transacting factor or factors with similar binding specificities.

Topics: Animals; Base Sequence; Breast Neoplasms; Cell Line; Cell Nucleus; Cholecystokinin; DNA; Enhancer Elements, Genetic; Exons; Female; Genes; Humans; Molecular Sequence Data; Oligonucleotide Probes; Promoter Regions, Genetic; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-fos; Proto-Oncogenes; Rats; Restriction Mapping; Sequence Homology, Nucleic Acid; Transcription, Genetic

Previous studies of the relationship between dietary fat and breast cancer have produced conflicting results and have provided no definitive evidence of a mechanistic link between fat and breast tumorigenesis. We conducted a study to compare postprandial levels of prolactin (Prl), a hormone suspected of promoting the growth of some human breast cancer, and several gut hormones, i.e., gastrin (Gs), vasoactive intestinal polypeptide (VIP), neurotensin (Nt), and cholecystokinin (CCK), following high- and low-fat isocaloric test meals. Data were obtained in the posttreatment period from 13 patients with breast cancer (nine stage I and four stage II), who were disease free clinically, and nine healthy controls. Subjects admitted to the research unit on 2 days were given the high-fat meal on day 1 and the low-fat meal on day 2. Blood samples were drawn before (i.e., fasting) and after test meal consumption. All hormone analyses were performed by radioimmunoassay. Results indicated a significant rise in postprandial Prl levels for stage II patients, but not for stage I patients or the controls. Postprandial Gs levels were also elevated, whereas VIP levels were markedly reduced in patients versus controls; these differences were most marked in stage II patients. No significant intergroup differences were noted in postprandial levels of Nt and CCK. Hormone levels of patients and controls did not differ between the test meal situations, which indicated that some other component of the test meals might have been responsible for altered Prl and Gs levels. The differences observed between the stage I and II patients indicated that diet may influence the aggressiveness of tumor behavior and development through alterations in postprandial hormone release.

Topics: Breast Neoplasms; Cholecystokinin; Dietary Fats; Eating; Female; Gastrins; Gastrointestinal Hormones; Humans; Neoplasm Staging; Neurotensin; Prolactin; Vasoactive Intestinal Peptide