- Potential Anti-Cyclin D1 Therapy for Breast Cancer
- Sentinel Lymph Node Biopsy and Molecular Analysis in the Management of Breast Cancer
- Does Exercise Really Help during Chemotherapy?
- RNA Polymerase II in the Act of Transcription
Cyclin D1 is a member of the cyclin family of proteins, which are part of the cell-cycle machinery. The majority of human breast cancers overexpress cyclin D1. Breast Cancer Research Program Award recipient, Piotr Sicinski of the Dana Farber Cancer Institute, had previously developed genetically-modified mice lacking cyclin D1, and had found that these mice develop essentially normally. This finding, along with the evidence of a role for cyclin D1 in breast cancer, suggested to the investigator that the removal of cyclin D1 might selectively shut off the proliferation of breast tumor cells, while sparing other cells. To test this idea, Dr. Sicinski and his colleagues crossed the mice lacking cyclin D1 with four different strains of cancer-prone, genetically-modified mice. The strains used overexpress the v-Ha-Ras, Neu, Myc, or Wnt-1 oncogenes. The researchers found that animals lacking cyclin D1 were resistant to breast cancers induced by the Neu and Ras oncogenes. In contrast, the cyclin D1-deficient mice were fully susceptible to breast cancers induced by the Myc, and Wnt-1. These results showed that in mammary epithelial cells, the Neu-Ras pathway is completely dependent on cyclin D1 for malignant transformation in mammary glands. Therefore, it might be possible to design highly specific anti-cyclin D1 therapy for treating human breast cancers that overexpress Neu-Ras.
Yu Q, Geng Y, Sicinski P. 2001. Specific protection against breast cancers by cyclin D1 ablation. Nature, 411(6841):1017-21.
Sentinel Lymph Node Biopsy and Molecular Analysis in the Management of Breast Cancer
Posted October 8, 2001
Kathryn M. Verbanac, Ph.D. and Lorraine Tafra, M.D., East Carolina University
Fiscal Years 1997 and 1999
Sentinel lymph node biopsy (SLNB) is a minimally invasive technique that was first used in the management of melanoma to identify those lymph nodes most likely to contain metastatic disease (i.e., cancer cells that have spread to other parts of the body). It was shown that if these sentinel nodes do not contain metastases, then the probability that other nodes contain metastases is negligible. Thus, for those patients whose cancer has not spread to other parts of the body, the morbidity associated with total lymph node removal could be avoided. Fiscal year 1997 Breast Cancer Research Program (BCRP) award recipients at East Carolina University were among the first in the world to implement SLNB in breast cancer patients and are now conducting a multi-institutional study to assess the accuracy of this technique in the management of breast cancer. Results support the general utility of SLNB in the care of breast cancer, establishing factors that play an important role in SLNB including patient age, surgical experience, and tumor location, as well as those factors that are irrelevant including prior surgery of the breast and tumor size. A fiscal year 1999 BCRP award made to these investigators expands the scope of their work to develop and evaluate more sensitive molecular assays to detect cancer biomarkers in sentinel lymph node and blood. These assays will be compared to the immunohistochemical and staining techniques currently used to analyze SLNB samples, and their prognostic value will be determined. The hypothesis is that molecular analysis will provide a more sensitive and accurate detection of metastases than conventional methods, which miss disease in many patients. Thus, BCRP investigators are laying the groundwork that will guide the medical community in appropriate application of SLNB to detect the spread of breast cancer.
Verbanac KM. 2001. Molecular detection of breast cancer markers. Molecular Diagnosis, 6(2):73-77.
Tafra L, Lannin DR, Swanson MS, Van Eyk JJ, Verbanac KM, Chua AN, Ng PC, Edwards MS, Halliday BE, Henry CA, Sommers LM, Carman CM, Molin MR, Yurko JE, Perry RR, and Williams R. 2001. Multicenter trial of sentinel node biopsy for breast cancer using both technetium sulfur colloid and isosulfan blue dye. Annals of Surgery, 233(1):51-59.
Tafra L, McMasters KM, Whitworth P, and Edwards MJ. 2000. Credentialing issues with sentinel lymph node staging for breast cancer. American Journal of Surgery, 180(4):268-273.
Verbanac KM, Min CJ, Purser SM, Swanson MS, Lo K, Albrecht J, and Tafra L. 2000. RT-PCR analysis for mammaglobin and carcinoembryonic antigen detects metastases in histology-negative lymph nodes. Breast Cancer Research & Treatment, 64:37, #106.
Min CJ, Tafra L, and Verbanac KM. 1998. Identification of superior markers for polymerase chain reaction detection of breast cancer metastases in sentinel lymph nodes. Cancer Research, 58(20):4581-4584.
Women who are undergoing chemotherapy for breast cancer often experience fatigue and weight gain. Breast Cancer Research Program grant recipient, Dr. Anna Schwartz, of the Oregon Health & Sciences University, while conducting research at the University of Utah, enrolled 78 breast cancer patients in an 8-week, low-intensity exercise regimen. She examined (1) the daily pattern of fatigue over the first three cycles of chemotherapy, and (2) the effect of exercise on body weight and fatigue. Dr. Schwartz determined that women who exercised as instructed experienced significantly less post-treatment fatigue than those who did not exercise. In addition, she found that women who exercised did not gain weight, while women who did not exercise experienced significant increases in weight. She also determined that women who exercised experienced a 15 percent increase in functional ability, while women who did not exercise demonstrated a 22.5 percent decrease in functional ability.
Schwartz AL, Mori M, Gao R, Nail LM, King B, and Madsen S. Exercise reduces daily fatigue in women with breast cancer receiving chemotherapy. Medicine and Science in Sports and Exercise 2001, 33(5):718-23.
Schwartz AL, Nail LM, Chen SL, Meek P, Barsevick AM, King ME, and Jones LS. Fatigue patterns observed in patients receiving chemotherapy and radiotherapy. Cancer Investigation 2000, 18(1):11-19.
Schwartz AL. Daily fatigue pattern and effect of exercise in women with breast cancer receiving chemotherapy. Cancer Practice 2000, 8(1):16-24.
Schwartz AL. Fatigue mediates the effect of exercise on quality of life in women with breast cancer. Quality of Life Research 1999, 8(6):529-38.
The transcription of DNA to RNA, the intermediate step in the pathway from genes to proteins, is accomplished by the enzyme complex RNA polymerase II. Transcription provides a key regulatory point for controlling gene expression. Understanding the basic mechanisms of transcription and its regulation may prove key to understanding, and hopefully combating, the altered gene expression characteristic of many tumors. The work of Breast Cancer Research Program Award recipient Averell Gnatt of the University of Maryland while in the laboratory of Dr. Roger Kornberg at Stanford University has led to a refined molecular structure (a sort of blueprint) of the yeast RNA polymerase II complex "in the act" of transcribing DNA. The structure was devised from x-ray crystallography studies of an elongation complex that comprises RNA polymerase II, DNA, and RNA. To obtain the crystals for these studies, Dr. Gnatt had to overcome major obstacles relating to the large size of the complex, difficulties in initiating such a complex in vitro, and eliminating inactive contaminants. The structure defines regions of the protein and intermolecular interactions involved in unwinding the DNA template, the entry and addition of ribonucleotides to the newly transcribed RNA strand, binding the DNA-RNA hybrid, and the separation and release of DNA and RNA strands. One striking finding was the closure of a "clamp" over the template and transcript in an active complex. The achievement of this structure will clearly facilitate the design of future studies that may help explain the disregulation of gene expression in breast cancer and other tumors.
Gnatt AL, Cramer P, Fu J, Bushnell DA, Kornberg RD. Structural basis of transcription: An RNA polymerase II elongation complex at 3.3 ? resolution. Science 2001 June 8, 292:1876-82.
Cramer P, Bushnell DA, Fu J, Gnatt AL, Maier-Davis B, Thompson NE, Burgess RR, Edwards AM, David PR, Kornberg RD. Architecture of RNA polymerase II and implications for the transcription mechanism. Science 2000, 288:640-9.
Fu J, Gnatt AL, Bushnell DA, Jensen GJ, Thompson NE, Burgess RR, David P, Kornberg RD. Yeast RNA polymerase II at 5 A° resolution. Cell 1999, 98:799-810.
Poglitsch CL, Meredith GD, Gnatt AL, Jensen GJ, Chang W, Fu J, Kornberg RD. Electron crystal structure of an RNA polymerase II transcription elongation complex. Cell 1999, 98:791-8.