Sam G. Pappas

Stable transfection of an estrogen receptor beta cDNA isoform into MDA-MB-231 breast cancer cells

We previously reported stable transfection of estrogen receptor alpha (ERalpha) into the ER-negative MDA-MB-231 cells (S30) as a tool to examine the mechanism of action of estrogen and antiestrogens [J. Natl. Cancer Inst. 84 (1992) 580]. To examine the mechanism of ERbeta action directly, we have similarly created ERbeta stable transfectants in MDA-MB-231 cells. MDA-MB-231 cells were stably transfected with ERbeta cDNA and clones were screened by estrogen response element (ERE)-luciferase assay and ERbeta mRNA expression was quantified by real-time RT-PCR. Three stable MDA-MB-231/ERbeta clones were compared with S30 cells with respect to their growth properties, ability to activate ERE- and activating protein-1 (AP-1) luciferase reporter constructs, and the ability to activate the endogenous ER-regulated transforming growth factor alpha (TGFalpha) gene. ERbeta6 and ERbeta27 clones express 300-400-fold and the ERbeta41 clone express 1600-fold higher ERbeta mRNA levels compared with untransfected MDA-MB-231 cells. Unlike S30 cells, 17beta-estradiol (E2) does not inhibit ERbeta41 cell growth. ERE-luciferase activity is induced six-fold by E2 whereas neither 4-hydroxytamoxifen (4-OHT) nor ICI 182, 780 activated an AP-1-luciferase reporter. TGFalpha mRNA is induced in response to E2, but not in response to 4-OHT. MDA-MB-231/ERbeta clones exhibit distinct characteristics from S30 cells including growth properties and the ability to induce TGFalpha gene expression. Furthermore, ERbeta, at least in the context of the MDA-MB-231 cellular milieu, does not enhance AP-1 activity in the presence of antiestrogens. In summary, the availability of both ERalpha and ERbeta stable breast cancer cell lines now allows us to compare and contrast the long-term consequences of individual signal transduction pathways.

Chemoprevention of breast cancer: current and future prospects.

The groundwork for making the concept of breast cancer chemoprevention a clinical reality began over a century ago. Although tamoxifens first clinical use was for the treatment of breast cancer, the earliest animal studies with the drug provided the scientific basis for chemoprevention. The extensive clinical experience, safety and laboratory data have made tamoxifen the current standard-of-care for the prevention of breast cancer in women at elevated risk. The STAR trial will address the value of raloxifene as a chemopreventative in postmenopausal women. Results will be available by 2005. Newer compounds are under development which hold the promise of expanded efficacy and narrower side-effect profile. These compounds will function as multifunctional medicines and will hold the promise of preventing breast and endometrial cancer, while providing the beneficial effects of preventing osteoporosis and coronary heart disease.

Raloxifene for the treatment and prevention of breast cancer

Raloxifene is a member of a family of drugs known as selective estrogen receptor modulators (SERMs). Raloxifene is currently approved by the FDA for the prevention and treatment of osteoporosis in postmenopausal women. SERMs hold the potential to treat and prevent breast cancer, osteoporosis and coronary heart disease. Ongoing clinical trials are in place to address the role of raloxifene and SERMs in each of these areas. We review the pharmacology, clinical utility, safety and tolerability of raloxifene and speculate on what the future holds for SERMs and their use in breast cancer.

Pathologic quiz case: a cystic pancreatic mass discovered in a patient with ileocecal carcinoid.

A white man with a prior history of coronary artery disease underwent a screening colonoscopy and was found to have an ileocecal carcinoid tumor that was proven by biopsy. A staging computed tomographic scan demonstrated the mass to be near the terminal ileum. In addition, another cystic mass located in the tail of the pancreas was seen (Figure 1, arrow). The patient’s preoperative laboratory values, including serum

Liver-directed therapy for primary and metastatic liver tumors

Preface. 1. Clinical Features of Primary and Metastatic Hepatic Malignancies S.G. Pappas, et al. 2. Pathologic Features of Primary and Metastatic Hepatic Malignancies M.Li-Cheng Wu. 3. Radiologic Imaging and Staging of Primary and Metastatic Liver Tumors J.W. Berlin. 4. Results of Surgical Resection for Hepatocellular Carcinoma S.M. Jones, M.D. Roh 5. Indications and Results of Liver Transplantation for Primary and Metastatic Liver Cancer A. Koffron. 6. Chemoembolization and Interstitial Therapies for Hepatocellular Carcinoma D.M. Rose, W.C. Chapman. 7. Diagnosis and Management of Intrahepatic and Extrahepatic Cholangiocarcinoma S.A. Curley. 8. Gallbladder Cancer L.G. Dawes. 9. Malignant Biliary Obstruction: Endoscopic Approaches W.G. Parsons, R. Alasadi. 10. Biology of Liver Metastases R.S. Berman, et al. 11. Results of Surgical Resection for Metastatic Liver Tumors S.F. Sener. 12. Resection for Recurrent Colorectal Liver Metastases K. Avradopolous, et al. 13. Surgical Resection of Hepatic Tumors - Patient Selection and Technical Considerations G.W. Daneker, Jr., C.A. Staley. 14. Radiofrequency Ablation for Primary and Metastatic Liver Tumors T.M. Pawlik, K.K. Tanabe. 15. Cryosurgery for Primary and Metastatic Liver Tumors J.L. Peacock. 16. Hepatic Artery Infusional Chemotherapy for Colorectal Liver Metastases A.R. Sasson, J.C. Watson. 16. Pediatric Liver Tumors M. Reynolds. Index.

Clinical Features of Primary and Metastatic Hepatic Malignancies

In the United States, it is estimated that 1,268,000 new cancer cases will be diagnosed in the year 2001. Approximately 550,000 cancer-related deaths will occur in the same time period (1). Cancers with the liver as a major site of disease involvement will constitute a significant portion (16,200 new cases) of these new cancer cases. Of concern is the typically poor response of primary liver tumors and hepatic metastases to conventional therapies. However, more aggressive operative strategies and the expanding use of regional and systemic chemotherapeutic approaches have led to more treatment options for tumors of the liver.

Resection for Recurrent Colorectal Liver Metastases

Colorectal cancer is one of the most common gastrointestinal cancers worldwide. It is estimated that in the year 2001, 130,200 colorectal cases will be diagnosed in the United States. Also over the next year, 56,300 Americans will die of this disease. Colorectal cancer ranks third in estimated cancer deaths, behind lung and prostate cancer in men, and lung and breast cancer in women (1). The vast majority of these patients die of metastases (2,3). Among patients diagnosed with colorectal cancer, during the course of their illness, the liver will become involved in 40-70% of cases. It has been well documented that the treatment of choice, on first presentation of hepatic metastases, is surgical resection (4–7). Numerous series report 5-year survival rates of 22%–39%, with an average around 30% (4–7). Unfortunately, this means that 70% of patients will recur after hepatic resection for colorectal metastases. Among these patients, about 30% will present with liver only recurrences, and about one third to one half of these will be candidates for a second hepatic resection (2,3).