When that day comes, Promega hopes to have played a supporting role.

The Need

More than 1.2 million people around the world will be diagnosed with breast cancer this year. It is the most common malignancy among women worldwide (1). In the US alone, the incidence rate has increased from one in 20 in 1960 to one in eight today. In some aspects scientists are already making considerable gains. Breast cancer death rates have been dropping steadily since 1990 thanks to continued discoveries that have paved the way for earlier detection and better treatments.

The Commitment to Find New Therapies

This complex and heterogenous disease is being investigated from numerous angles - genetic, physiological and environmental. Last year alone more than 20,000 research papers were published investigating subjects as diverse as the effect of inherited mutations, the mechanisms of cell cycle regulation, the elucidation of DNA repair and signaling pathways within cancer cells, the investigation of the role of hormone receptors, the search for cancer-specific markers, and the development of more sensitive methods for the detection of disseminated tumor cells.

The eventual unraveling of the molecular signatures of various types of cancer cells holds tremendous promise as a means to identify effective therapies or a cure. Knowledge of the cellular mechanisms involved in the development of individual cancers raises the possibility of treatment based on specific inhibitors, antibodies, vaccines, or gene therapy, and has already led to the development of therapeutic agents, such as monoclonal antibodies (2-4) and aromatase inhibitors such as anastrozole and others (5,6), which were developed directly as a result of the identification of specific molecular targets within cancer cells.

Such critical leaps in our knowledge represent the culmination of many years of painstaking research and cannot be achieved without the contributions of many unsung heroes. Their body of work, often involving the step-by-step elucidation of seemingly small parts of complex molecular pathways, forms the foundation from which such leaps are made.

Recent Discoveries

It is often said that the journey of a thousand miles begins with a single step. The enormous complexity of the group of diseases characterized as breast cancer means that the journey towards elucidation of its causes and appropriate therapies/preventative strategies is of necessity composed of many, many, small steps. This web highlights a small selection of recent papers investigating various aspects of the disease, each illuminating its own part of the next step on the road to the journey’s end. Use the links under "Breast Cancer Research Today" on the right to view summaries of these research papers. Click on "More Breast Cancer Citations" to browse through a larger selection of recent papers.

References

1. Hortobagyi, G.N., et al. (2005) The global breast cancer burden: variations in epidemiology and survival. Clin. Breast Cancer 6, 391–401.
2. Baslega, J. (2001) Clinical trials of Herceptin (trastuzumab). Eur. J. Cancer 37, S18-24.
3. Slamon, D.J. et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783-92.
4. Esteva, F.J. (2004) Monoclonal antibodies, small molecules and vaccines in the treatment of breast cancer. The Oncologist, 9 (suppl 3), 4-9.
5. Kendall, A., and Dowsett, M. (2006) Novel concepts for the chemoprevention of breast cancer through aromatase inhibition. Endocrine-Related Cancer 13, 827-37.
6. Bange, J., Zwick, E., and Ullrich, A. (2001) Molecular targets for breast cancer therapy and prevention. Nature Med. 7, 548-51.
 

First Report of Regulation of Expression of Human ERα by a Specific microRNA in a Breast Cancer Cell Line

Lack of expression of the estrogen receptor ERα has been associated with poor prognosis in breast cancer, as ERα –negative cancer cells undergo proliferation that is not dependent on estrogen stimulation and is not susceptible to treatment with hormonal therapies such as selective estrogen receptor modulators. Published in the March 13 online issue of Molecular Endocrinology, a study by Adams, Furneaux and White of the University of Connecticut Health Center showed that the microRNA miR-206 binds to specific regions in the 3´ UTR of the ERα  gene, and is able to repress ERα expression in a breast cancer cell line. The authors used real-time PCR, RNA interference, and luciferase reporter assays to demonstrate regulation of ERα expression by binding of the microRNA to its target sites.

Citation: Adams, B.D., Furneaux, H. and White, B. (2007) The micro-RNA miR-206 targets the human estrogen receptor-α, and represses ERα mRNA and protein expression in breast cancer cells. Mol. Endocrinol. Mar. 13 Epub (ahead of print).

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Implications of a Specific Metabolic Profile for Treatment

The March 2007 issue of Cancer Research contains a paper by Chen et al., of the Scripps Research Institute and the Interdisciplinary Research Center at Justus-Liebig University, Germany, comparing the protein expression profiles that distinguish breast cancer cells with a propensity to metastasize to the brain with those from bone metastases and from circulating tumor cells. The authors identified a set of proteins differentially expressed in cells from brain lesions, most of which were involved in oxidative energy metabolism, suggesting an adaptation of these cells to derive energy from glucose oxidation. The association of these differentially expressed proteins with brain localization and the implications of this metabolic profile for future treatment options are discussed. These authors used large-scale proteomic analysis, real-time PCR, and a luminescence-based ATP assay to effectively evaluate the expression profiles of the brain tumor cells. 

Citation: Chen, E.I., Hewel, J., Kreuger, J.S., Tiraby, C., Weber, M.R., Kralli, A., Becker, K., Yates, J.R., and Felding-Habermann, B. (2007) Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res. 67, 1472-1486.

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Exploiting Weaknesses in DNA Repair

Defective DNA repair pathway mechanisms are a characteristic of certain tumors. Therefore, an understanding of the specific pathways that are damaged in breast cancer cells raises the possibility of exploiting key steps in these pathways to render tumor cells more sensitive to treatments that cause DNA damage, such as ionizing radiation. Cells defective in BRCA1 and BRCA2 are deficient in their ability to repair double-stranded DNA breaks by homologous recombination, and are also sensitive to inhibition of poly(ADP-Ribose) polymerase (PARP) activity. McCabe et al., in the August 2006 issue of Cancer Research, investigated the basis of this PARP inhibition sensitivity, specifically looking at whether the role of BRCA1 and 2 in homologous recombination might be an underlying factor. Using small molecule inhibitors of PARP activity, and techniques such as immunofluorescence, FACS analysis and a luminescent cell viability assay, the authors showed that role of BRCA1 and BRCA2 in homologous recombination contributes to the sensitivity to PARP inhibition.

Citation: McCabe, N., Turner, N.C., Lord, C.J., Kluzek, K., Bialkowska, A., Swift, S., Giavara, S., O'Connor, M.J., Tutt, A.N., Zdzienicka, M.Z., Smith, G.C.M., and Ashworth, A. (2006) Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-Ribose) polymerase inhibition. Cancer Res. 66, 8109-8115.

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Possibility that BRCA1 Can Regulate Estrogen Biosynthesis in Adipose Tissue

A recent study by Ghosh et al., from the University of Virginia and from Fudan University in Shanghai, investigated the relationship between the tumor suppressor BRCA1 and the aromatase gene. The rate limiting step in the synthesis of estrogen from androgen is catalyzed by the aromatase enzyme, and aromatase inhibitors are used in the treatment of postmenopausal breast cancer. Obesity-associated elevated estrogen increases the risk for breast cancer in postmenopausal women. Normally aromatase is expressed under a weak promoter in adipose tissue; however in breast cancer a second, strong ovary-specific promoter (PII) drives expression. This study investigated the relationship of BRCA1 and aromatase expression. The authors showed that siRNA knockdown of BRCA1 resulted in activation of the PII promoter, suggesting that BRCA1 can modulate estrogen biosynthesis in adipose tissue.

Citation: Ghosh, S., Lu, Y., Katz, A., Hu, Y., and Li, R. (2007) Tumor suppressor BRCA1 inhibits a breast cancer-associated promoter of the aromatase gene (CYP19) in human adipose stromal cells. Am. J. Physiol. Endocrinol. Metab. 292, E246-E252.

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Searching For Sensitive Methods to Detect Metastasis

In a paper published in the British Journal of Cancer in February 2006, Benoy et al., from the University of Antwerp, used real-time PCR to detect disseminated tumor cells and compared the sensitivity and detection rates between bone marrow and less invasive peripheral blood sampling procedures. Probes for the epithelial cell marker cytokeratin-19 (CK-19) and the breast-tissue specific marker mammaglobin (MAM) were used. Peripheral blood and bone marrow samples were collected from 148 patients with varying stages of breast cancer, before initiation of treatment. Occurrence of elevated CK-19 or MAM expression in the bone marrow was associated with a poor prognosis. The results indicated that only the presence of disseminated tumor cells in the bone marrow could be correlated with overall survival. The presence of circulating CK-19 or MAM+ cells in the peripheral blood did not appear to be as reliable a tool for predicting disease outcome.

Citation: Benoy, I.H., Elst, H., Philips, M., Wuyts, H., Van Dam, P., Scharpe, S., Van Marck, E., Vermeulen, P.B., and Dirix, L.Y. (2006) Real-Time RT-PCR detection of disseminated tumor cell in bone marrow has superior prognostic significance in comparison with circulating tumour cells in patients with breast cancer. Br. J. Cancer 94, 672-80.

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