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At least 19 recordsLinked to original sources
PubMed1992

The gene encoding the human spasmolytic protein (SML1/hSP) is in 21q 22.3, physically linked to the homologous breast cancer marker gene BCEI/pS2.

The human spasmolytic protein, SML1/hSP, an inhibitor of spasmolytic activity and gastric acid secretion in the pig, has been shown to exhibit homology to the pS2 protein, an estrogen-dependent breast cancer marker. Moreover, SML1/hSP and pS2 are expressed at the same localization in the normal stomach and during healing of the gastrointestinal tract. Here we report the chromosomal localization, obtained by in situ hybridization, of the hSP gene (SML1) to chromosome 21 at 21q22.3. Using pulsed-field gel electrophoresis, we found SML1 to be within 230 kb of the BCEI/pS2 gene.

Biomarkers, Tumor↗
PubMedDate not supplied

The bovine pancreatic spasmolytic polypeptide gene maps to syntenic group U10: implications for the evolution of the human breast cancer estrogen inducible locus.

Recently, homology has been reported for pS2, a protein expressed in many human breast cancers, and a hormonogastric protein known as pancreatic spasmolytic polypeptide (SPP; formerly designated as PSP). The breast cancer estrogen inducible locus (BCEI), which encodes pS2, maps to human chromosome 21 (HSA 21). The SPP locus has not been mapped in humans. Several loci from HSA 21 have been mapped in cattle to syntenic group U10, but a BCEI bovine homolog was not detected. If a bovine BCEI locus does exist, map comparisons predict BCEI will reside on syntenic group U10. The assignment of bovine SPP to syntenic group U10 supports the postulated evolutionary relationship between BCEI and SPP.

Animals↗
PubMed1992

Trefoil peptide expression in intestinal adaptation and renewal.

There are many avenues where molecular biology is important in studying the gut, and here we explore methods for defining expression of a new gene family in the gut. We have defined the pattern of trefoil peptide gene expression in the ulceration-associated cell lineage (UACL) and in the nearby mucosa in Crohn's disease. In the UACL, human spasmolytic polypeptide mRNA and peptide are expressed in the acinar and proximal duct cells, whereas pS2 mRNA and peptide are found in the distal duct cells and in the surface cells. In adjacent mucosa, pS2 mRNA and protein are expressed ectopically by goblet cells. Ultrastructural immunolocalisation showed the pS2 to be co-packaged in the mucous cell granules. pS2 peptide was demonstrated in local neuroendocrine cells and was also co-packaged with the neuroendocrine granules. The crypts associated with the UACL also showed marked neuroendocrine cell hyperplasia. We have also cloned the newest trefoil peptide intestinal trefoil factor from human and rat intestinal mucosa and shown its co-expression with mucus by normal intestinal goblet cells. The co-packaging of the same secretory protein in both mucous and neuroendocrine granules, which have different functions, is unusual and indicates an important role for pS2 in the secretory process itself or as a ligand delivered to its receptor via multiple routes. We conclude that the trefoil peptides are widely distributed in the intestine in inflammatory bowel disease and are of considerable potential functional importance.

Amino Acid Sequence↗
PubMed1992

Trefoil peptide gene expression in gastrointestinal epithelial cells in inflammatory bowel disease.

Trefoil peptides are a growing group of proteins with interesting structural and functional properties. We have defined the pattern of trefoil peptide gene expression in the ulceration-associated cell lineage (UACL) and in the nearby mucosa in Crohn's disease. In the UACL, human spasmolytic polypeptide (hSP) mRNA is expressed in the acinar and proximal duct cells, while pS2 mRNA and peptide are found in the distal duct cells and in the surface cells. In adjacent mucosa, pS2 mRNA and protein are expressed by goblet cells, with the pS2 peptide concentrated in the area of the Golgi and also in the theca. Ultrastructural immunolocalisation showed the pS2 to be co-packaged in the mucous cell granules before being secreted into the intestinal lumen. In addition, pS2 peptide was demonstrated in local neuroendocrine cells and was also co-packaged with the neuroendocrine granules. The crypts associated with the UACL also showed marked neuroendocrine cell hyperplasia. We conclude that pS2 peptide is secreted locally into the viscoelastic coat covering the intestinal mucosa which surrounds Crohn's disease ulcers. In addition, it is clear that intestinal goblet cells, in addition to producing mucins, are a rich source of regulatory peptides. Moreover, pS2 is clearly co-packaged with neurosecretory granules, which are released through basal and lateral membranes so that the contained peptides can act in a paracrine manner. These findings are interpreted in terms of the epidermal growth factor/urogastrone released by the UACL, stimulating pS2 gene expression in surrounding cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Crohn Disease↗
PubMed1992

Association of the human spasmolytic polypeptide and an estrogen-induced breast cancer protein (pS2) with human pancreatic carcinoma.

The human pS2 gene, isolated from the breast carcinoma cell line MCF-7 and shown to be under estrogen transcriptional control in a subclass of breast cancer cells was reported to be secreted in normal stomach surface epithelial cells, whereas additional gastrointestinal tissues like pancreas and colon do not secrete pS2 at all. In porcine pancreas, a spasmolytic polypeptide (sharing domains of homology with pS2) was observed; a corresponding human gene (hSP) was shown to be active in normal stomach mucosa. hSP and pS2 gene activity in normal and neoplastic pancreas tissues was then compared. Whereas both genes are inactive in normal pancreatic cells, activation of the pS2 sequence in a primary pancreatic carcinoma cell culture and in 23 tumor tissues was noted when investigated by immunostaining. In all cases when pS2 showed a regular 0.6 kb transcript, hSP displayed a transcript of 0.7 kb. Six of these tumors showed a reduced pS2 immunoreactivity and, at the same time, aberrant pS2 mRNA bands and a complete shut-down of the hSP gene were noted. In one case, whereas normal pancreas remained negative, the corresponding tumor and its metastasis displayed regular transcripts of pS2 and hSP. This remarkably high correlation suggests that pS2 and hSP expression in the pancreatic tumors, but not in their corresponding healthy tissue is significantly linked to molecular steps leading to tumorigenesis.

Adenocarcinoma↗
PubMed1992

Enzyme-linked immunosorbent assay of pS2 in breast cancers, benign tumors, and normal breast tissues. Correlation with prognosis and adjuvant hormone therapy.

An enzyme-linked immunosorbent assay using monoclonal and polyclonal antibodies against recombinant pS2 was devised. It was used to measure pS2 concentration in the cytosol of 339 breast cancer, 15 fibroadenomas, 16 cases of benign breast disease, and 6 normal breast tissues. The mean value of pS2 concentration was higher in cancer, but the protein could be detected readily in benign tumors and even in normal breast. The concentration of pS2 was significantly lower in postmenopausal women and tumors of differentiation Grade 3. The pS2 concentration was correlated strongly with the presence of estrogen receptors (ER) and progesterone receptors (PR). No correlation was observed with the size, histologic type of the tumor, and lymph node status. The prognostic value of pS2 appeared relatively limited. It was clear cut only for a relatively small group of patients (approximately 15%), who had low concentrations of pS2 (less than or equal to 0.32 ng/mg of protein). These patients had a shorter disease-free interval and overall survival time. The most striking correlation was observed with the outcome of adjuvant hormone therapy. pS2 concentration was shown to be the most potent prognostic factor, preceding even ER.

Adult↗
PubMed1992

Cowden's disease. A case report with analyses at the molecular level.

Cowden's disease (multiple hamartoma syndrome) is characterized by multiple hamartomas of ectodermal, endodermal, and mesodermal origin, a high incidence of malignant tumors of the breast and/or thyroid gland, and an autosomal dominant pattern of inheritance. Similar to sporadic breast cancer, chromosomal studies have not elucidated the cause of this syndrome. The authors report the case of a patient with this syndrome and analyze the pattern of amplification or rearrangement of three genes: the HER-2/neu oncogene, the ras oncogene, and the estrogen-inducible gene, pS-2. All three of these genes were present in single copies without translocations. It was noteworthy that three of the most important genes currently studied in relation to breast cancer existed in a unamplified unrearranged state in this patient. Those with clinical manifestations of Cowden's disease may be candidates for prophylactic bilateral total mastectomy, and the authors recommend that these patients undergo this procedure by their third decade of life. An alternative to this approach would entail monthly self examinations, breast examinations by the patient's physician every 3 months, bilateral mammograms every 6 to 12 months, and biopsy of any suspicious lesions. It is crucial, however, that these patients be identified by their mucocutaneous lesions and family history before an underlying malignant lesion develops.

Adult↗
PubMed1992

An immunohistochemical survey of pS2 expression in human epithelial cancers.

The oestrogen-inducible pS2 protein isolated from human breast-cancer cells appears to have prognostic significance in breast-cancer patients. Using both monoclonal and polyclonal pS2 anti-sera, we have carried out an immunocytochemical survey of 9 epithelial cancers. Some degree of specific tumour staining was observed in 4 tissues, the extent varying greatly between specimens. Most (11/13) of the colorectal cancers showed immunoreactivity, as did 4/5 pancreatic carcinomas. In some of these cases, patchy staining was also observed in adjacent non-tumour cells. Two bronchio-alveolar carcinomas showed positivity, but 5 poorly differentiated adenocarcinomas of the lung did not. In the ovary, staining was observed in 3/3 mucinous cystadenocarcinomas but only in 1/8 of the serous type. No reactivity was seen in specimens of salivary gland, kidney, liver, prostate or uterus. This pilot study indicates that pS2 may be a useful marker of adenocarcinomas in human neoplasms apart from those in the breast, and suggests that more extensive surveys might be worthwhile.

Adenocarcinoma↗
PubMed1992

pS2 protein and steroid hormone receptors in invasive breast carcinomas.

We have used immunohistochemical and hormone-binding techniques to determine the presence of estrogen receptors, estrogen-receptor protein, progesterone receptors and pS2 protein in 97 invasive breast cancers. Our group of tumors displayed the same frequency of estrogen receptors and progesterone receptors as other comparable groups, but it contained more tumors containing pS2 protein. We also observed staining of morphologically normal cells in lobules adjacent to the tumors and in several fibroadenomas; both findings vary from some other reports. We attribute these variations to the use of a sensitive immunohistochemical method and choice of the lowest possible threshold to classify a tumor as pS2-positive. If we used a higher threshold, then about 95% of the tumors containing pS2 protein also contained estrogen receptor protein. Our results add further weight to the assertion that tumors containing pS2 protein also display estrogen receptors. The data also provide theoretical and indirect support to the clinical prediction that tumors containing pS2 protein are more likely to respond to hormonal therapy and may have a more indolent course than tumors lacking the molecule.

Adult↗
PubMed1991

Antipeptide antibodies against the pNR-2 oestrogen-regulated protein of human breast cancer cells and detection of pNR-2 expression in normal tissues by immunohistochemistry.

Five peptides, corresponding to regions of the predicted protein sequence of the oestrogen-regulated pNR-2 protein which is expressed in oestrogen-responsive human breast cancer cells, were synthesized. Two peptides were immunogenic in rabbits and antisera against one peptide reacted with the pNR-2 protein in sections of formalin-fixed, paraffin-embedded breast tumour. There was a significant correlation between the extent of pNR-2 protein expression detected by immunohistochemistry and pNR-2 mRNA levels determined by hybridization with a cDNA probe in a series of primary breast tumours. pNR-2 expression was assessed immunohistochemically in a panel of normal tissues. Expression was detected in normal breast, small intestine, and stomach (body and antrum).

Amino Acid Sequence↗
PubMed1992

The distribution of PSA, cathepsin-D, and pS2 in BPH and cancer of the prostate.

In view of the limitations associated with the present tumor markers for prostate cancer, we have examined the potential expression of two further markers, Cathepsin-D and pS2, in human prostate and attempted to link their concentrations with the histopathology of the tissue, the PSA levels and the androgenic status of the gland. Cathepsin-D and pS2 were measured in cytosol fractions obtained from 22 patients with benign prostatic hyperplasia (BPH) and 20 patients with prostate cancer (CaP) employing immunoassays specific for these markers. The concentrations of Cathepsin-D (BPH: mean +/- SEM = 18.50 +/- 1.88 nmol/g protein; CaP = 19.75 +/- 2.49 nmol/g protein) and pS2 (BPH = 1,024.7 +/- 348.06 ng/g protein; CaP = 1,513.88 +/- 268.60 ng/g protein) were not different in the two tissue types, whereas PSA in BPH tissue (1,952.27 +/- 249.93 micrograms/g protein) was significantly higher than the measurements in CaP (583.75 +/- 104.33 micrograms/g protein). However, none of the tumor marker concentrations correlated with the degree of differentiation of the tumors, and we were unable to establish any correlation with the levels of testosterone and dihydrotestosterone in the tissue. In conclusion, although Cathepsin-D and pS2 are expressed in prostate tissue, it is doubtful whether they will have an active role in the management of prostate cancer.

Cathepsin D↗
PubMed1992

pS2 expression in primary breast carcinomas: relationship to clinical and histological features and survival.

pS2 protein expression has been reported to have prognostic significance in human breast carcinomas and to correlate with estrogen receptor positivity, although these findings have not been confirmed by all investigators. pS2 positivity was compared to various clinical and histologic parameters in a retrospective study of 290 patients (median follow-up 7.2 years) and significantly correlated with tumor grade and estrogen receptor content (p = 0.001 and p = 0.0007, respectively). Significant associations between pS2 positivity and lymph node metastases, T stage, histologic tumor type, and patient age were not observed. Univariate and multivariate analyses (controlling for estrogen receptor content, T and N stage) of the patient population at large showed that pS2 positivity was not predictive of disease-free or overall survival. Univariate analysis of lymph node negative patients demonstrated that both pS2 and estrogen receptor positivity were significantly associated with a better outcome. Multivariate analysis of these patients, however, showed that only estrogen receptor data had independent prognostic significance. This study suggests that immunohistochemical analysis for pS2 protein expression will not contribute additional prognostic information if the estrogen receptor content is known.

Age Factors↗
PubMed1992

Prognostic relevance of pS2 status in association with steroid receptor status and proliferative activity in node-negative breast cancer.

Expression of the oestrogen-regulated pS2 protein was investigated on paraffin-embedded sections of primary breast tumours from 200 node-negative patients. Immunoreactivity was observed in 56% of the cases. pS2 expression was inversely correlated with tumour size and proliferative activity, whereas a direct correlation was observed with steroid receptor. 5-year relapse free survival was influenced by tumour size (P = 0.02), oestrogen receptor status (P less than 0.05), and proliferative activity (P less than 0.01). No difference in relapse-free survival was observed between patients subdivided according to pS2 expression alone. However, among patients with oestrogen-receptor-negative tumors, pS2 expression predicted a shorter relapse-free survival.

Breast Neoplasms↗
PubMed1992

Expression of c-erbB2, TGF-beta 1 and pS2 genes in primary human breast cancers.

The presence of c-erbB2, TGF-beta 1 and pS2 mRNAs was examined in primary breast tumours. The c-erbB2 mRNA was overexpressed in 34% of the tumours. There was a positive, statistically significant correlation between c-erbB2 gene overexpression and nodal status. TGF-beta 1 mRNA was detected in 84% of the tumours, regardless of their clinical status. When possible, the c-erbB2 and TGF-beta 1 proteins were identified immunohistochemically on frozen sections from the same tumours. For TGF-beta 1, the mRNA and immunohistochemical results were divergent in 6 cases, 5 of which did contain clearly detectable mRNA but did not stain with the antibody. The pS2 mRNA was detected in 22% of the tumours and in the BT474 cell line. There was a significant correlation between the presence of pS2 mRNA and of oestrogen receptors. No statistically significant correlation was observed between pS2 and TGF-beta 1 genes expression and the clinical parameters of the tumours.

Aged↗
PubMed1992

Bile acids influence the growth, oestrogen receptor and oestrogen-regulated proteins of MCF-7 human breast cancer cells.

The effects of the major human serum bile acid, glycochenodeoxycholic acid (GCDC), as well as unconjugated chenodeoxycholic acid (CDC), on the MCF-7 human breast cancer cell line have been studied in vitro under oestrogen and bile acid deprived culture conditions. GCDC increased the growth of the breast cancer cells over the range 10-300 microM. At concentrations in excess of the bile acid binding capacity of the medium cell growth was prevented. In contrast 10 microM CDC tended to reduce cell growth. Oestrogen (ER) and progesterone (PgR) receptors, pS2 and total cathepsin D were quantified by monoclonal antibody based immunoassays. Ten to 100 microM GCDC and 10 microM CDC down-regulated ER protein and this was accompanied by induction of the oestrogen-regulated proteins PgR, pS2 and possibly cathepsin D, including increased secretion of the latter two proteins into the culture medium. All these changes were quantitatively similar to those observed with 10 nM oestradiol. The bile acid effects on ER and PgR were not due to interference with the assay procedures. Cells incubated with 50 microM GCDC or 10 microM CDC had higher pmolar concentrations of the bile acids than controls. This study suggests that naturally occurring bile acids influence the growth and steroid receptor function of human breast cancer cells.

Bile Acids and Salts↗
PubMedDate not supplied

Inflammatory breast carcinoma: an immunohistochemical study using monoclonal anti-pHER-2/neu, pS2, cathepsin, ER and PR.

Immunocytochemical assays were performed on frozen sections of inflammatory breast carcinomas (n = 22) using the following monoclonal antibodies (MoAb): anti-pHER2/neu, cathepsin, pS2, ER, PR and MoAb Ki67. The distribution of these proteins, known as prognostic indicators, was evaluated with an image analysis system (SAMBA, Alcatel TITN, France). On standard HE stained paraffin sections, only about 50% of inflammatory breast tumors exhibited intradermal tumor cell emboli. All tumors were strongly pHER/2neu positive. All tumors also, but to a lesser degree, were cathepsin and ki67 positive. Conversely, less than 40% were faintly ER, PR and pS2 immunoreactive. The results correlated with the high degree of malignancy of inflammatory breast carcinomas. Therefore the immuno-detection of these markers in addition to standard histological techniques appears to be a useful tool to evaluate the degree of malignancy of breast carcinomas.

Antibodies, Monoclonal↗