gastrins and Breast-Neoplasms

We report a case of metastatic gastrinoma to the breast morphologically mimicking solid papillary carcinoma of the breast. A 59-year-old woman presented with a hypoechoic right breast mass that histologically revealed solid nests of small monotonous tumor cells, fibrovascular cores, and round to oval nuclei with fine chromatin and small nucleoli. Immunohistochemistry demonstrated chromogranin and synaptophysin positivity. Tumor prognostic markers showed weak positivity for estrogen receptor and negativity for progesterone receptor. Although an initial diagnosis of solid papillary carcinoma was rendered, subsequent identification of the patient's clinical history of pancreatic gastrinoma and an additional immunohistochemical stain for gastrin supported a diagnosis of metastatic gastrinoma. We report this rare case to increase awareness of metastatic neuroendocrine tumors in the breast. Multiple breast lesions and lack of expression of estrogen/progesterone hormone receptors should prompt careful review of the patient's clinical history to rule out metastatic neuroendocrine disease.

Topics: Biomarkers, Tumor; Biopsy; Breast Neoplasms; Carcinoma, Papillary; Chromogranins; Diagnosis, Differential; Female; Gastrinoma; Gastrins; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Middle Aged; Pancreatic Neoplasms; Predictive Value of Tests; Receptors, Estrogen; Receptors, Progesterone; Synaptophysin

The association of motilin, ghrelin, leptin, gastrin, pepsinogen (PG) I and II with cancer chemotherapy-associated dyspepsia syndrome (CADS) was investigated in 35 patients with breast cancer receiving first cycle of 5-fluorouracil, cyclophosphamide, epirubicin (FEC60) chemotherapy.. The onset of dyspeptic symptoms on days 3 and 10 after chemotherapy identified patients with and without CADS. Gastrointestinal symptoms were scored with the Gastrointestinal Symptom Scoring Rate (GSRS) questionnaire. Gastrointestinal peptides were evaluated by enzyme-linked immunosorbent assay.. Twenty-one patients (60%) had CADS. The area under the curve (AUC) of ghrelin was higher, whereas that of PGI, PGII and motilin were lower in patients with CADS compared to those without. In patients with CADS, the AUC of PGI and PGII negatively correlated with the GSRS indigestion cluster.. Impairment of gastrointestinal motility suggested by low motilin concentrations and mucosal damage mirrored by an increase of ghrelin seem to be involved in the onset of CADS in patients during chemotherapy for breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Cyclophosphamide; Dyspepsia; Epirubicin; Female; Fluorouracil; Follow-Up Studies; Gastrins; Gastrointestinal Motility; Gastrointestinal Tract; Ghrelin; Humans; Leptin; Middle Aged; Motilin; Neoplasm Staging; Pepsinogen A; Pepsinogen C; Peptide Fragments; Prognosis; Prospective Studies; Syndrome

The overexpression of HER-2/neu is an independent prognostic factor of clinical outcome of breast cancer, therefore determination of HER-2/neu status is now an integral part of the clinicopathologic workup. The ways of measuring the copy number of the HER-2/neu gene in tumor cells comprise in situ hybridization techniques and real-time polymerase chain reaction (PCR). Quantitative real-time PCR is a relatively new technique for assessing HER-2/neu gene amplification with high sensitivity. However, the HER-2/neu Quantification Kit developed by Roche designed for a LightCycler 1.5 platform had been withdrawn from the commercial market; therefore, we were encouraged to design an alternative LightCycler-based method that offers the desired level of reliability. One hundred breast cancer cases with known HER-2/neu status have been examined with the original Roche developed HER-2/neu Quantification kit and the custom real-time PCR assay. The newly developed, custom PCR showed sensitivity of 91.43%, specificity of 90.63%, and accuracy of 90.91% taking fluorescence in situ hybridization results as the end point. We have described a novel real-time PCR technique for the relative quantification of the HER2/neu gene on a LightCycler 1.5 platform. We have determined that our method is eligible and ideal for the supplement of regular fluorescence in situ hybridization reactions, concerning its high sensitivity and reliability.

Topics: Base Sequence; Breast Neoplasms; Gastrins; Gene Amplification; Gene Dosage; Humans; In Situ Hybridization, Fluorescence; Molecular Sequence Data; Polymerase Chain Reaction; Prognosis; Receptor, ErbB-2; Sensitivity and Specificity

Topics: Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Carcinoma; Cytokines; Gastrins; Gastrointestinal Neoplasms; Helicobacter Infections; Humans; Lung Neoplasms; Mast Cells; Neoplasm Metastasis; Stress, Physiological

Analysis of an 83-year-old male presenting with diarrhoea showed secretory diarrhoea. serum levels of gastrin and pancreatic polypeptide were elevated. Somatostatin-receptor scintigraphy revealed a hot spot in the left thoracic wall and subsequently, breast adenocarcinoma with neuroendocrine differentiation was diagnosed. Postoperatively, the patient made an uneventful recovery. The relationship between the clinical picture, the results of pathological examination and hormonal analysis is discussed and put into perspective.

Topics: Aged, 80 and over; Breast Neoplasms; Diarrhea; Gastrins; Humans; Male; Neuroendocrine Tumors; Pancreatic Polypeptide

Previous studies showed that antagonists of bombesin (BN)/gastrin-releasing peptide (GRP) inhibit the growth of various cancers by interfering with the growth-stimulatory effects of BN-like peptides and down-regulating epidermal growth factor receptors on tumors. Because the overexpression of the human epidermal growth factor receptor-2 (ErbB-2/HER-2/neu) oncogene plays a role in the progression of many breast cancers, we investigated whether BN/GRP antagonists can affect HER-2 in mammary tumors. Female nude mice bearing orthotopic xenografts of MDA-MB-435 human estrogen-independent breast cancers were treated daily with BN/GRP antagonists RC-3095 (20 microg) or RC-3940-II (10 microg) for 6 weeks. The expression of BN/GRP receptors on tumors was analyzed by reverse transcription-PCR and immunoblotting. We also evaluated whether the mRNA expression for the c-jun and c-fos oncogenes is affected by the therapy. Both BN/GRP antagonists significantly inhibited growth of MDA-MB-435 cancers; RC-3095 reduced tumor volume by 40% and RC-3940-II by 65%. The GRP receptors (subtype 1) were detected in MDA-MB-435 tumors, showing that they mediate the inhibitory effect of the antagonists. Tumor inhibition was associated with a substantial reduction in the expression of mRNA and protein levels of the ErbB/HER receptor family as well as with a decrease in the expression of c-jun and c-fos oncogenes. BN/GRP antagonists RC-3940-II and RC-3095 could be considered for endocrine therapy of estrogen-independent breast cancers that express members of the ErbB/HER receptor family and the c-jun and c-fos oncogenes.

Topics: Adult; Animals; Bombesin; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Division; Epidermal Growth Factor; Estrogens; Female; Gastrins; Gene Expression Regulation, Neoplastic; Genes, fos; Genes, jun; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Peptide Fragments; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Receptor, ErbB-2; RNA, Messenger; Tumor Cells, Cultured

Our recent studies using comparative genomic hybridization showed that gain or amplification at the 17q12-q21 region is very common in the intestinal type of gastric cancer. Here, we describe a fluorescence in situ hybridization study with gastrin (GAS)-specific and ERBB2-specific probes on ten specimens of gastric carcinoma that, by using comparative genomic hybridization, showed 1) DNA copy number gain or amplification at 17q12-q21, a region known to harbor the GAS and ERBB2 genes (four cases); 2) gain of the entire chromosome 17 (three cases); or 3) normal copy number of chromosome 17 (three cases). GAS and ERBB2 protein expression was studied by Western immunoblotting from gastric cancer cell lines with or without gain at 17q12-q21 as well as a breast cancer cell line with ERBB2 amplification. Our results showed that simultaneous amplification of both GAS and ERBB2 was four- to ninefold in the tumors with the 17q12-q21 amplification. Both genes were amplified in the same nuclei, and the hybridization signals were localized to the same region of the nucleus. Overexpression of GAS and ERBB2 was observed by Western immunoblotting only in the gastric cancer cell line with gain at 17q12-q21. The ERBB2 amplification is also a recurrent change in breast cancer. To investigate whether the GAS amplification is unique in gastric cancer, fluorescence in situ hybridization analysis was performed on 40 breast cancer cell lines. The ERBB2 amplification was observed in 11 cell lines, but none of the lines showed the GAS amplification. This indicates that the formation of an amplicon, in which both the GAS and the ERBB2 genes are amplified, might be unique in gastric cancer, especially in its intestinal type, and that simultaneous amplification of both genes is important to the tumorigenesis of intestinal gastric cancer. We demonstrate here for the first time that a gene of a physiological hormone is amplified in tumors that originate from cells that normally secrete the hormone.

Topics: Breast Neoplasms; Carcinoma; Chromosomes, Human, Pair 17; Gastrins; Gastrointestinal Neoplasms; Gene Amplification; Humans; In Situ Hybridization, Fluorescence; Receptor, ErbB-2; Tumor Cells, Cultured

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

Topics: Base Sequence; Breast Neoplasms; DNA Primers; DNA, Neoplasm; Female; Flow Cytometry; Gastrins; Gene Amplification; Gene Expression; Humans; In Situ Hybridization, Fluorescence; Molecular Sequence Data; Oncogenes; Phenotype; Point Mutation; Polymerase Chain Reaction; Reference Standards

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

Environmental factors promote the development of and decrease survival from Breast Cancer. Prospective morphological and hormonal studies indicate biological markers for this disease are evident in premenopausal women. The majority of premenopausal patients are non-obese (Body Mass Index, BMI less than 25). Lean women have a greater proportion of estrogen receptor negative (ER-) tumours, which may grow faster and have a higher concentration of epithelial growth factor (EGF). We have reported that lean, BMI less than 23, versus obese, BMI greater than 28, women have a different gut-pancreatic peptide hormone response to meals and that differences in these peptide hormones occur between healthy and age weight matched premenopausal patients. We hypothesize that the diet peptide hormone control of food intake in lean women is associated with the development of mammary dysplasia, change in growth factor profile and steroid hormone metabolism.

Topics: Breast Neoplasms; Female; Food Preferences; Gastrins; Humans; Menopause; Pancreatic Hormones; Receptors, Estrogen; Thinness

The expression of NSE and hormone immunoreactivity were examined in lymph node metastases from 15 primary breast carcinomas (6 NSE-positive and 9 NSE-negative). NSE immunoreactivity was expressed in metastases in 7 cases. Both the primary tumour and lymph node metastasis(es) were NSE-positive in 3 cases. In 4 cases NSE-negative primary tumours were associated with NSE-positive lymph node metastases. In 2 of the 7 cases with NSE-positive metastases, the metastatic lesions did not express uniform NSE immunoreactivity. Immunoreactivity for hormones (gastrin (1 case), prealbumin (2 cases), ACTH and beta-endorphin (1 case) and somatostatin (1 case] was present in 5 of the 7 NSE-positive lymph node metastatic lesions. In one case only the same hormone (gastrin) was expressed in both the primary tumour and its lymph node metastasis. The present study shows that no relationship exists between primary tumours and the corresponding lymph node metastases with regard to NSE and hormone immunoreactivity.

Topics: Adrenocorticotropic Hormone; Breast Neoplasms; Enkephalin, Leucine; Gastrins; Hormones; Humans; Lymphatic Metastasis; Phosphopyruvate Hydratase

Eight mucinous carcinomas of the breast were studied by light microscopy and immunohistochemistry; one was studied by electron microscopy. All 8 cases had abundant, relatively clear cytoplasm that contained mucin. Cells were argyrophil positive and argentaffin negative. Eight cases were positive for neuron specific enolase (NSE), 5 cases for serotonin, 1 case for serotonin and somatostatin and 2 cases for serotonin, somatostatin, and gastrin. None had clinical evidence of abnormal neuroendocrine function. Three patients had axillary lymph node metastases. Only 1 of 5 patients in whom there was clinical followup died of her disease. Electron microscopy of one case showed abundant intracytoplasmic and extracellular mucin, round and pleomorphic dense-core granules, numerous cell processes, and aggregates of intermediate filaments. These cases expand the histologic spectrum of breast carcinomas which may show neuroendocrine differentiation.

Topics: Adenocarcinoma, Mucinous; Breast Neoplasms; Cytoplasm; Gastrins; Histocytochemistry; Humans; Immunochemistry; Microscopy, Electron; Mucins; Neurosecretory Systems; Serotonin; Somatostatin

Thirty-eight infiltrating ductal carcinomas, nine infiltrating lobular carcinomas, two tubular carcinomas and one papillary carcinoma were studied by light microscopy, immunocytochemistry and electron microscopy. Seventeen cases showed immunoreactivity for NSE. Immunostaining for different peptide-hormones was observed in 12 of these 17 cases and in none of the 10 NSE-negative cases used for controls. Scattered cells were positive for gastrin in five cases, pancreatic polypeptide in five, leu-enkephalin in three, sub-P in two, ACTH in one, bombesin in one and beta-endorphin in one case. Four cases revealed immunoreactivity for more than one peptide-hormone. Typical neuroendocrine granules were seen in five cases (all positively stained for NSE). Small, electron dense granules of possible neuroendocrine nature were not found in any of the 33 NSE-negative tumours. Our results confirm that immunoreactivity for NSE is present in a high proportion of breast carcinomas, but that neuroendocrine differentiation cannot be proved to be present in all these cases.

Topics: Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Papillary; Cross Reactions; Female; Gastrins; Humans; Immunoenzyme Techniques; Microscopy, Electron; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Serotonin

Topics: 5-Hydroxytryptophan; Adrenocorticotropic Hormone; Breast Neoplasms; Calcitonin; Chorionic Gonadotropin; Erythropoietin; Estradiol; Female; Gastrins; Hormones, Ectopic; Humans; Hyperkalemia; Middle Aged; Neoplasm Metastasis; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone; Progesterone