Marker In Human Breast Cancer Research Articles

Monitering for recurrence or metastasis and evaluating the therapic effect by tumor marker for human breast cancer

Monitering for recurrence or metastasis and evaluating the therapic effect by tumor marker for human breast cancer

Constitutive Tyrosine Phosphorylation of ErbB-2 via Jak2 by Autocrine Secretion of Prolactin in Human Breast Cancer

Overexpression of the oncogene for ErbB-2 is an unfavorable prognostic marker in human breast cancer. Its oncogenic potential appears to depend on the state of tyrosine phosphorylation. However, the mechanisms by which ErbB-2 is constitutively tyrosine-phosphorylated in human breast cancer are poorly understood. We now show that human breast carcinoma samples with ErbB-2 overexpression have higher proliferative and metastatic activity in the presence of autocrine secretion of prolactin (PRL). By using a neutralizing antibody or dominant negative (DN) strategies or specific inhibitors, we also show that activation of Janus kinase Jak2 by autocrine secretion of PRL is one of the significant components of constitutive tyrosine phosphorylation of ErbB-2, its association with Grb2 and activation of mitogen-activated protein (MAP) kinase in human breast cancer cell lines that overexpress ErbB-2. Furthermore, the neutralizing anti-PRL antibody or erbB-2 antisense oligonucleotide or DN Jak2 or Jak2 inhibitor or DNRas or MAP kinase kinase inhibitor inhibits the proliferation of both untreated and PRL-treated cells. Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation. The identification of this novel cross-talk between ErbB-2 and the autocrine growth stimulatory loop for PRL may provide new targets for therapeutic and preventive intervention of human breast cancer.

Alternatively spliced MDM2 transcripts in human breast cancer in relation to tumor necrosis and lymph node involvement.

Several short forms of alternatively spliced Murine double minute 2 (MDM2) transcripts have recently been shown to correlate with high-grade malignancy in a number of human tumors. We examined the frequency of splice variants and their correlation with clinicopathological features in 60 cases of human breast cancer. Seven short forms coexpressed with wild-type mRNA were detected by nested RT-PCR. Sequencing of all the MDM2 variants demonstrated mRNA splicing which disrupted not only the conserved p53-binding domain but also, further towards the carboxy-terminus, the conserved nuclear localization sequence and/or the acidic and zinc finger domains. There was no significant correlation between the coexpression of splice variants and tumor size, histologic type or hormone (estrogen and progesterone) receptor status. However, cases with spliced MDM2 transcripts tended to be of a more aggressive type with axillary lymph node involvement and extensive necrosis in the tumors. Although the functional significance of MDM2 variants remains obscure, we anticipate that these variants will be confirmed as a novel prognostic marker in human breast cancer.

Comparison of the metastasis-inducing protein S100A4 (p9ka) with other prognostic markers in human breast cancer

Comparison of the metastasis-inducing protein S100A4 (p9ka) with other prognostic markers in human breast cancer

Comparison of the metastasis-inducing protein S100A4 (p9ka) with other prognostic markers in human breast cancer

Our aim was to compare the occurrence and prognostic significance over 14-20 years of immunocytochemically detected S100A4 and other tumour variables in primary tumours from 349 patients with operable breast cancer. For a cut-off of 1% staining of the malignant cells, the antibody to S100A4 stains positively 56% of the carcinomas. There was a significant association of staining for S100A4 with tumours fixed to the chest wall, staining for c-erbB-2, c-erbB-3, pS2, cathepsin D and, inversely, at borderline levels with staining for estrogen receptor. Using Wilcoxon statistics in univariate analyses, staining for S100A4, nodal status, tumour class, histological grade and staining for c-erbB-2, p53 were associated negatively and staining for estrogen receptor, progesterone receptor were associated positively with patient survival times. The survival times of patients with S100A4-negative carcinomas with or without one of the other tumour variables showed no significant differences, whilst those of patients with S100A4-positive carcinomas showed significant differences in a negative or a positive way. Multivariate regression analysis for 137 patients showed that staining for S100A4 is most highly correlated with patient deaths, but involved lymph nodes, fixed tumours, high histological grade and staining for progesterone receptor were also significant independent prognostic variables. Our results suggest that in this set of patients, the tumour variable most tightly correlated with patient death is S100A4.

A Mouse Model for Breast Cancer Induced by Amplification and Overexpression of the neu Promoter and Transgene

ErbB-2 is a critical oncogenic marker in human breast cancer. Its appearance correlates with poor prognosis and it is, therefore, an important target for physiologic investigation and therapeutic intervention. With this in mind, we have created and characterized two mouse breast cancer models that express rat wild type neu, the homologue of ErbB-2, and rat mutant neu under the control of the normal mouse neu promoter. These models in which the copy number of the neu gene is moderately amplified should more closely parallel the expression pattern of ErbB-2 seen in some cases of human breast cancer. Transgenic mouse models were constructed by injecting one of the two pronuclei of a fertilized FVB/n egg and implanting it into a pseudopregnant Swiss /Webster mouse. Tissue expression was analyzed through the use of reverse transcription polymerase chain reaction and mammary histopathology examined by fixing, staining and mounting of the entire gland. In the former wild type model, we show that low level, long term expression of neu leads to abnormal lobuloalveolar development in virginal glands and incomplete regression in multiparous glands. Malignant foci form following multiple rounds of pregnancy and regression. In the latter model, a similarly directed transgene carrying the constitutively activated, mutant form of the rat neu gene, a stronger but similar phenotype is displayed. Evidently minor perturbations in amplified neu expression are sufficient to alter mammary development and induce malignant transformation.

In vivo bromodeoxyuridine (BrdUrd) labeling index as a prognostic marker in human breast cancer

In vivo bromodeoxyuridine (BrdUrd) labeling index as a prognostic marker in human breast cancer

A second trefoil protein, ITF/hP1.B, is transcribed in human breast cancer.

Trefoil proteins form a specific group of stable secreted polypeptides. They are expressed in a lot of human cancers and during inflammatory processes of the gastrointestinal tract. Recently a new human trefoil protein, ITF/hP1.B, was isolated. Until now no studies of the activity of this gene in human solid tumors exist. In our examination we show for the first time that this gene is transcribed in human breast cancer. In contrast to another trefoil protein, pS2, the expression of ITF/hP1.B is not under control of estrogen in the human breast cancer cell line MCF-7. We suggest that the gene activity of ITF/hP1.B in addition to pS2 expression may be an improved prognostic marker in human breast cancer.

ErbB-2 antisense oligonucleotides inhibit the proliferation of breast carcinoma cells with erbB-2 oncogene amplification

Amplification and overexpression of the erbB-2 oncogene is an unfavourable prognostic marker in human breast cancer and occurs in approximately 25% of breast carcinomas. We used erbB-2 antisense oligonucleotides to inhibit the proliferation of human breast cancer cell lines. erbB-2 antisense oligonucleotides (20 microM) inhibited the growth and DNA synthesis of breast cancer cell lines with an amplified erbB-2 gene by up to 60%. Control complementary sense oligonucleotides did not inhibit cellular proliferation at the same concentration but showed inhibitory effects at higher concentrations. There was no specific effect of erbB-2 antisense oligonucleotides on breast cancer cell lines that had no amplification of erbB-2. erbB-2 antisense oligonucleotides reduced erbB-2 protein levels, measured by immunohistochemistry, in a dose-dependent manner. erbB-2 sense oligonucleotides did not decrease the levels of erbB-2 protein. These data indicate that erbB-2 antisense oligonucleotides induce a specific inhibition of erbB-2 protein expression and that erbB-2 gene overexpression is important for the proliferation of the breast cancer cells that have been selected for erbB-2 amplification.

PLASMINOGEN ACTIVATORS IN BREAST-CANCER CELLS

This review summarizes recent experimental and clinical studies on plasminogen activator (PA) expression in breast cancer cells. The two PAs, urokinase-type (u-PA) and tissue-type (t-PA), have quite different biological significance in breast cancer cells. Sufficient evidence indicates that t-PA production is regulated by estrogen via an estrogen receptor system and suggests the potential usefulness of this enzyme as a marker for estrogen action in breast cancer cells. On the other hand, u-PA has been implicated in cancer cell invasion and metastasis formation because this enzyme can degrade components of the extracellular matrices and basement membranes either directly through its enzyme activity or indirectly by activation of other proteinases. High levels of u-PA correlates with both shortened disease-free survival and overall survival in patients with breast cancer indicating that u-PA is a new prognostic marker in human breast cancer. In contrast to u-PA, t-PA is associated with a good prognosis. However, t-PA is involved in bone-only metastasis formation by its effects through the vertebral venous plexus.

Lineage infidelity and expression of melanocytic markers in human breast cancer

In previous analyses, dual expression of melanocytic and epithelial molecular markers have been described as indicators of lineage infidelity for breast cancer cells that lose their epithelial identity. Here we demonstrated that this is a much more frequent phenomenon in human breast carcinomas, usually affecting only a part of the tumor. Accordingly we detected, in 18 out of 100 breast carcinomas, immunohistochemically focally positive cells for the melanocytic marker Melan A. The presence and extent of Melan A expression was statistically significantly associated with a reduction in tumor cell differentiation, but not tumor type, size, lymph node metastasis, hormone receptor status or Her-2-neu expression. Microarrays of a further 159 breast cancers showed, in several samples, variably low expression levels of Melan A (and other melanocytic markers) that are consistent with focal expression in many tumors. One case strongly overexpressed Melan A. The transition from an epithelial to a melanocytic phenotype (lineage infidelity) appears to occur much more frequently than previously assumed and occurs in restricted areas of breast cancer during tumor progression, a possible association with a reduction in tumor cell differentiation.

Expression of genes coding for pS2, c-erbB2, estrogen receptor and the H23 breast tumor-associated antigen: A comparative analysis in breast cancer

Expression of the gene coding for a new breast tumor-associated antigen, H23, was compared to expression of genes coding for pS2, c-erbB2 and estrogen receptor (ER). Comparison involved mRNA expression in normal and malignant breast tissues as well as in non-breast tumors. Results obtained by RNA dot blot and Northern hybridizations showed that expression of the H23 antigen coding gene is a discriminatory marker in human breast cancer. It is expressed in 92% of breast tumors whereas 69%, 62% and 56% of breast tumors demonstrate significant mRNA levels of c-erbB2, ER and pS2, respectively. Non-malignant or normal breast tissue expresses much lower levels of the H23 antigen mRNA. From the comparative analysis presented here it is concluded that the gene coding for H23 antigen furnishes a most useful marker for human breast cancer.

Conversion to estriol in “normal”, benign and malignant human breast tissues

Since there are controversial reports in the literature on 16 alpha-hydroxylase activity in human breast tumors, we have studied this enzyme activity in "normal", benign and malignant breast tissues by measuring the conversion of estradiol to estriol. Whereas 8 out of 14 (58%) malignant tumors showed positive activity, none of the other tissues had any detectable 16 alpha-hydroxylase activity. These preliminary results, when combined with reports in the literature on animal and human tissues, appear to indicate that more extensive studies on this enzyme could be useful as it could be an additional metabolic marker in human breast cancer.

Epidermal growth factor receptors in human breast cancer.

The capacity for specific binding of 125I-epidermal growth factor (EGF) was studied in crude membrane fractions from 95 human breast carcinomas. About 42% of the samples showed saturable, high affinity, specific binding of EGF. In 21% of the tumors we were able to demonstrate high (above 10 fmoles/mg protein) binding capacity. Moreover, high EGF receptor values were associated with a low content of estradiol receptor. These studies are related to the definition of new biochemical markers in human breast cancer.

The investigation of lactalbumin as a possible marker for human breast cancer

Measurable amounts of the whey protein lactalbumin have been found in the cytosol of over a third of 89 primary breast carcinomas using a specific radioimmunoassay. With a modification of the method which prevents interference from endogenous antibodies, serum levels of lactalbumin have been measured in 83 subjects with breast cancer, 45 subjects with benign mammary dysplasic and 63 controls. In earlier studies of normal women, we found that circulating lactalbumin was not found in subjects aged over 45 yr but was commonly present below that age. Since the patients with benign dysplasia had a mean age of 35.0 yr and the breast carcinoma patients a mean age of 60.4 yr, separate control groups were necessary for the two patient groups. Circulating lactalbumin was found in 12% of patients with operable breast cancer, 24% of patients with metastatic disease and in none of the age-matched controls. Circulating lactalbumin was detected no more often in the patients with benign dysplasia than in corresponding controls. It appears that a sizeable minority of human breast carcinomas are able to synthesise lactalbumin in sufficient quantity to produce a measurable level in the blood.

Estrogen Receptors and Post-Receptor Markers in Human Breast Cancer: A Reappraisal

Several major defects in the estrogen receptor pathway have been evidenced in most human breast cancers by an immunofluorescence tracing of estradiol receptor complexes at the single cell level. Endogenous peroxidase seems a reliable postreceptor marker for estrogen-sensitive breast cancer cells. Since almost all human breast cancers appear to include both hormone-sensitive and autonomous cell populations, a combined use of endocrine and cytotoxic regimens is urged. The hormonal regulation of tumor growth parameters could be exploited in order to achieve a maximum recruitment of synchronized tumor cells at risk to chemotherapy.

Interrelationships of mammalian hormones and enzyme levels in vivo.

Interrelationships of mammalian hormones and enzyme levels in vivo.H C Pitot, and M B YatvinH C Pitot, and M B YatvinPublished Online:01 Jan 1973https://doi.org/10.1152/physrev.1973.53.1.228MoreSectionsPDF (17 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Download PDF FiguresReferencesRelatedInformation Cited ByMetabolic zonation of the liver: Regulation and implications for liver functionPharmacology & Therapeutics, Vol. 53, No. 3Expression of cholinergic markers in the developing chick embryo spinal cordInternational Journal of Developmental Neuroscience, Vol. 4, No. 5Development of lipogenesis and insulin sensitivity in tissues of the ob/ob mouseM. L. Kaplan, and G. A. Leveille1 February 1981 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 240, No. 2Acetylcholinesterase activity in seven brain areas and adenohypophysis during the estrous cycleNeuroscience Letters, Vol. 19, No. 3Changes of glutamic acid decarboxylase activity after dexamethasone in selected areas of the rat brainNeuroscience Letters, Vol. 19, No. 1Unlinked control of multiple glucocorticoid-induced processes in HTC cellsMolecular and Cellular Endocrinology, Vol. 15, No. 3l-Tryptophan action on hepatic RNA synthesis and enzyme inductionMolecular and Cellular Biochemistry, Vol. 24, No. 3Cortisol dependent acute metabolic responses in rat liver cellsJournal of Steroid Biochemistry, Vol. 9, No. 5Effects of estradiol and testosterone on the activity of pyruvate kinase of the cardiac and skeletal muscles of rats as a function of age and sexBiochimica et Biophysica Acta (BBA) - General Subjects, Vol. 540, No. 1Estrogen Receptors and Post-Receptor Markers in Human Breast Cancer: A Reappraisal16 April 2018 | Tumori Journal, Vol. 64, No. 2Quantitative changes in the metabolism of 20α-hydroxy-4-pregnen-3-one by rat hypothalamus and pituitary during proestrusSteroids, Vol. 28, No. 4Liver protein synthesis. Molecular weight distribution of pulse-labeled polypeptide chains in normal and thyroidectomized ratsBiochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis, Vol. 425, No. 2Effects of dihydrotestosterone and estradiol benzoate pretreatment upon testosterone-induced sexual behavior in the castrated male ratHormones and Behavior, Vol. 6, No. 1Interaction of steroids with hepatoma cells: Molecular mechanisms of glucocorticoid hormone actionJournal of Steroid Biochemistry, Vol. 6, No. 1Effect of thyroxine on DNA synthesis and thymidine kinase activity during cerebellar developmentBrain Research, Vol. 78, No. 3Dietary induction of hepatic malic enzyme activity: Differentiation of the induction processLife Sciences, Vol. 14, No. 8Mechanism of action of glucocorticoidsMetabolism, Vol. 23, No. 2Metabolism of progesterone in rat uterusSteroids, Vol. 23, No. 1 More from this issue > Volume 53Issue 1January 1973Pages 228-325 Copyright & PermissionsCopyright © 1973 by American Physiological Societyhttps://doi.org/10.1152/physrev.1973.53.1.228PubMed4568413History Published online 1 January 1973 Published in print 1 January 1973 Metrics