Purpose To update the recommendations for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast cancer. Methods For the 2007 update, an Update Committee composed of members from the full Panel was formed to complete the review and analysis of data published since 1999. Computerized literature searches of MEDLINE and the Cochrane Collaboration Library were performed. The Update Committee’s literature review focused attention on available systematic reviews and metaanalyses of published tumor marker studies. In general, significant health outcomes (overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used for making recommendations. Recommendations and Conclusions

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American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer

Malignant cells are known to have accelerated metabolism, high glucose requirements, and increased glucose uptake. Transport of glucose across the plasma membrane of mammalian cells is the first rate-limiting step for glucose metabolism and is mediated by facilitative glucose transporter (GLUT) proteins. Increased glucose transport in malignant cells has been associated with increased and deregulated expression of glucose transporter proteins, with overexpression of GLUT1 and/or GLUT3 a characteristic feature. Oncogenic transformation of cultured mammalian cells causes a rapid increase of glucose transport and GLUT1 expression via interaction with GLUT1 promoter enhancer elements. In human studies, high levels of GLUT1 expression in tumors have been associated with poor survival. Studies indicate that glucose transport in breast cancer is not fully explained by GLUT1 or GLUT3 expression, suggesting involvement of another glucose transporter. Recently, a novel glucose transporter protein, GLUT12, has been found in breast and prostate cancers. In human breast and prostate tumors and cultured cells, GLUT12 is located intracellularly and at the cell surface. Trafficking of GLUT12 to the plasma membrane could therefore contribute to glucose uptake. Several factors have been implicated in the regulation of glucose transporter expression in breast cancer. Hypoxia can increase GLUT1 levels and glucose uptake. Estradiol and epidermal growth factor, both of which can play a role in breast cancer cell growth, increase glucose consumption. Estradiol and epidermal growth factor also increase GLUT12 protein levels in cultured breast cancer cells. Targeting GLUT12 could provide novel methods for detection and treatment of breast and prostate cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcp.20166

Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

Telomerase is a ribonucleoprotein enzyme that maintains the protective structures at the ends of eukaryotic chromosomes, called telomeres. In most human somatic cells, telomerase expression is repressed, and telomeres shorten progressively with each cell division. In contrast, most human tumors express telomerase, resulting in stabilized telomere length. These observations indicate that telomere maintenance is essential to the proliferation of tumor cells. We show here that expression of a mutant catalytic subunit of human telomerase results in complete inhibition of telomerase activity, reduction in telomere length and death of tumor cells. Moreover, expression of this mutant telomerase eliminated tumorigenicity in vivo. These observations demonstrate that disruption of telomere maintenance limits cellular lifespan in human cancer cells, thus validating human telomerase reverse transcriptase as an important target for the development of anti-neoplastic therapies.

Inhibition of telomerase limits the growth of human cancer cells

The MYC proto-oncogene encodes a ubiquitous transcription factor (c-MYC) involved in the control of cell proliferation and differentiation. Deregulated expression of c-MYC caused by gene amplification, retroviral insertion, or chromosomal translocation is associated with tumorigenesis. The function of c-MYC and its role in tumorigenesis are poorly understood because few c-MYC targets have been identified. Here we show that c-MYC has a direct role in induction of the activity of telomerase, the ribonucleoprotein complex expressed in proliferating and transformed cells, in which it preserves chromosome integrity by maintaining telomere length. c-MYC activates telomerase by inducing expression of its catalytic subunit, telomerase reverse transcriptase (TERT). Telomerase complex activity is dependent on TERT, a specialized type of reverse transcriptase. TERT and c-MYC are expressed in normal and transformed proliferating cells, downregulated in quiescent and terminally differentiated cells, and can both induce immortalization when constitutively expressed in transfected cells. Consistent with the recently reported association between MYC overexpression and induction of telomerase activity, we find here that the TERT promoter contains numerous c-MYC-binding sites that mediate TERT transcriptional activation. c-MYC-induced TERT expression is rapid and independent of cell proliferation and additional protein synthesis, consistent with direct transcriptional activation of TERT. Our results indicate that TERT is a target of c-MYC activity and identify a pathway linking cell proliferation and chromosome integrity in normal and neoplastic cells.

Direct activation of TERT transcription by c-MYC.

https://www.gastrojournal.org/article/S0016-5085(01)20970-6/pdf

Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver

PURPOSETo compare the prognostic impact of tumor angiogenesis factors (vascular endothelial growth factor [VEGF], angiogenin, and basic fibroblast growth factor [bFGF]), tumor proteolysis factors (urokinase-type plasminogen activator [uPA] and plasminogen activator inhibitor-1 [PAI-1]), and conventional tumor markers (stage, grade, and steroid receptors) in early breast cancer.PATIENTS AND METHODSIn the primary clinical study, tumor angiogenesis and other factors were detected in frozen biopsies from 305 primary breast tumors. VEGF expression was assessed by chemiluminescence immunosorbent assay (ICMA); angiogenin, bFGF, uPA, and PAI-1 by enzyme-linked immunosorbent assay (ELISA); and steroid receptors (estrogen receptor [ER] and progesterone receptor [PgR]) by enzyme immunoassay (EIA). In the validating clinical study, another set of 190 node-negative primary breast tumor samples were collected at a separate institution.RESULTSUnivariate analysis of the primary study showed that VEGF levels were positive...

Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients.

Telomerase, a ribonucleoprotein complex, adds hexameric repeats called telomeres to the growing ends of chromosomal DNA. The enzyme telomerase activity is present in a vast majority of tumors but is repressed in most normal tissues. Recently, two groups have reported the molecular cloning of the putative catalytic subunit (hEST2/hTRT) of the telomerase gene. We investigated the expression of this gene in diverse tumor-derived cell lines and tumors as well as in various normal tissues. The expression of hEST2/hTRT was detectable in tumor-derived cell lines, primary breast tumors, pancreatic tumors, and kidney tumors. Furthermore, the expression of hEST2/hTRT was down-regulated in response to a differentiation inducer. However, several normal tissues also expressed varying levels of hEST2/hTRT. Early passage cultures of endothelial fibroblasts and some epithelial cells also expressed the telomerase gene, albeit at low levels. In contrast, the expression of TLP1/TP1, the human homologue of Tetrahymena p80 telomerase subunit, was similar in all of these samples. Our results indicate that the differences in expression of hEST2/hTRT in tumor versus normal cells are relative and are not absolute.

https://cancerres.aacrjournals.org/content/canres/58/4/622.full.pdf

Expression Profile of the Putative Catalytic Subunit of the Telomerase Gene

Signaling through pathways involving mitogen-activated protein kinases (MAP kinases) has been implicated in the pathogenesis of cancer. Thus, the activity of MAP kinase is essential in the malignant potential of human breast tumors. p42/44(MAPK) was significantly higher expressed in tumor samples than in matching normal tissues adjacent to the tumor. p42/44(MAPK) protein expression correlated with enhanced MAP kinase activity only in a subset of tumors, indicating that over-expression of MAP kinases does not reflect the activation status of these enzymes. MAP kinase activity was significantly elevated in 131 tissue samples from primary breast tumors when compared to 18 normal tissues adjacent to tumors. A trend for higher MAP kinase activity in primary tumors of node-positive patients was observed when compared with tumors from node-negative patients. Similarly, higher MAP kinase activities were observed in specimens from patients who had a relapse within the follow-up time of 40 months when compared with patients with no relapse. A survival analysis demonstrated that the MAP kinase activity in primary breast tumors is potentially prognostic for relapse-free survival of patients.

Potential prognostic value of mitogen-activated protein kinase activity for disease-free survival of primary breast cancer patients.

https://www.gastrojournal.org/article/0016-5085(83)90026-4/pdf

Heinz Mueller

Papers

Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients.

Expression Profile of the Putative Catalytic Subunit of the Telomerase Gene

Potential prognostic value of mitogen-activated protein kinase activity for disease-free survival of primary breast cancer patients.

Hepatic Monooxygenase Activities in Subjects With a Genetic Defect in Drug Oxidation

Mutant p53 protein associated with chemosensitivity in breast cancer specimens.