Montclair Breast Center

Gene Therapy Week, 17 April 2008

Breast Cancer; Reports from Temple University describe recent advances in breast cancer

2008 APR 17 - (NewsRx.com) -- "We reported previously that the obesity hormone leptin is overexpressed in breast cancer biopsies. Here, we investigated molecular mechanisms involved in this process, focusing on conditions that are associated with obesity, that is, hyperinsulinemia and induction of hypoxia," investigators in the United States report (see also Breast Cancer).

"By using quantitative real-time PCR, immunofluorescent detection of proteins and enzyme-linked immunosorbent assays, we found that treatment of MCF-7 breast cancer cells with high doses of insulin or the hypoxia-mimetic agent CoCl2, or culturing the cells under hypoxic conditions significantly increased the expression of leptin mRNA and protein. Notably, the greatest leptin mRNA and protein expression were observed under combined hyperinsulinemia and hypoxia or hypoxia-mimetic treatments. Luciferase reporter assays suggested that increased leptin synthesis could be related to the activation of the leptin gene promoter. DNA affinity precipitation and chromatin immunoprecipitation experiments revealed that insulin, CoCl2 and/or hypoxia treatments augmented nuclear accumulation of hypoxia-inducible factor-1 alpha ( HIF-1 alpha) and increased its interaction with several upstream leptin regulatory sequences, especially with the proximal promoter containing four hypoxia-response elements and three GC-rich regions. By using reverse chromatin precipitation, we determined that loading of HIF-1 alpha on the proximal leptin promoter concurred with the recruitment of p300, the major HIF coactivator, suggesting that the HIF/p300 complex is involved in leptin transcription," wrote S. Cascio and colleagues, Temple University.

The researchers concluded: "The importance of HIF-1 alpha in insulin- and CoCl2-activated leptin mRNA and protein expression was confirmed using RNA interference."

Cascio and colleagues published their study in Oncogene (Mechanism of leptin expression in breast cancer cells: role of hypoxia-inducible factor-1 alpha. Oncogene, 2008;27(4):540-547).

For additional information, contact E. Surmacz, Temple University, Sbarro Institute Cancer Research & Molecular Medical, 1900 N, 12th St., Room 446, Philadelphia, PA 19122, USA.

The publisher of the journal Oncogene can be contacted at: Nature Publishing Group, Macmillan Building, 4 Crinan St., London N1 9XW, England.

Gene Therapy Weekly, March 6, 2008

Breast Cancer; Personalized medicine can cut breast cancer risk

(c) Copyright 2008 Gene Therapy Week via NewsRx.com
2008 MAR 6 - (NewsRx.com) -- The time has come for breast cancer risk assessment, counseling and genetic testing to move from cancer specialists to the realm of primary care, according to a presentation at the AAAS annual meeting, held this year in Boston (see also Breast Cancer).

"A growing body of evidence has documented the benefits of preventive measures for high-risk women including those with mutations in the BRCA1 and BRCA2 genes," said Funmi Olopade, MD, the Walter L Palmer Distinguished Service professor of medicine and director of the Cancer Risk Clinic at the University of Chicago Medical Center. "Referral for cancer-risk assessment and BRCA testing in the primary care setting is a necessary next step towards personalized medicine for women at risk for breast cancer."

Most high-risk women present in the primary care setting, she said. Primary care physicians should learn about the genetics of cancer risk, take a comprehensive personal and family history and advise patients who appear to be at increased risk about the plusses, minuses and limitations of genetic testing and risk-reduction strategies.

Physicians now have enough information to help patients understand the consequences of genetic testing, she added. Studies have found that genetic counseling and testing do not cause adverse psychological effects. There is convincing data on the risk reduction associated with prophylactic surgery—removal of the breasts and or ovaries to prevent cancer in those with known mutations. And preventive measures for those at risk now extend beyond pre-emptive surgery to intensive screening and chemoprevention.

"More than ten years after BRCA1 and BRCA2 were identified as major breast and ovarian cancer susceptibility genes," Olopade added, "primary care providers should embrace genetic risk assessment and BRCA mutation testing."

There is still a great deal that we don't know about these cancer-causing mutations, she added. The frequency and impact of BRCA1 and BRCA2 in various ethnic groups is still poorly understood, with conflicting results clouding the picture. As a consequence, genetic testing is underused by many ethnic groups.

Scientists are still finding new mutations of these genes. Some of these mutations increase disease risk and some may not. These genes may also interact with the environment or with other genes in ways that could modify their effects.

Even the methods of genetic testing can vary. Some tests look only for common mutations; others sequence the entire gene and look for tiny variations.

"There is still a great deal that we do not know about the role of these genes in inherited as well as sporadic breast cancer," said Olopade. "But we do know that mutation of these genes is common in families with hereditary breast cancer and among young women with breast cancer and that when we know a patient has a mutation there are several options to reduce the risk of breast cancer."

No other predictor is as powerful as an inherited mutation in the tumor-suppressor genes BRCA1 and BRCA2. "Our goal," Olopade said, "is to make this knowledge more and more available to patients, and that has to begin in the primary care setting. Only then can we hope to reap the benefits of individualized medicine."

Gene Therapy Weekly, September 20, 2007

Molecular Targets; The Molecular Profiling Institute Launches Mammostrat - a Novel, Molecular-Targeted, Prognostic Test for Breast Cancer Patients

2007 SEP 20 - ( NewsRx.com) -- The Molecular Profiling Institute, Inc. (Molecular Profiling) announced that they are now providing Mammostrat, a new molecular-targeted breast prognostic test, to breast cancer patients, nationwide. The Mammostrat prognostic test utilizes five immunohistochemical (IHC) biomarkers to classify patients into high-, moderate-, or low-risk categories for disease recurrence.

Robert Penny, M.D., Ph.D., the Chairman and CEO of the Molecular Profiling Institute stated, "Mammostrat will benefit the care of breast cancer patients nationwide by allowing their cancer to be quickly analyzed for prognosis by a direct light-microscopic evaluation of the cancer cells by a pathologist. This new test, which is performed on tissue preserved according to standard practice, streamlines the process for patients while providing the accuracy of direct visualization."

The test was developed by Applied Genomics, Inc. who rigorously translated recent genomic insights in cancer into a novel immunohistochemistry test. Mammostrat test results have been validated using over a thousand patient samples in North America from clinics/organizations such as the Cleveland Clinic Foundation and the National Surgical Adjuvant Breast and Bowel Project -- generating results with clear cut conclusions from multiple independent studies supporting the prognostic value of the test.

"We are excited to have partnered with the Molecular Profiling Institute, says Doug Ross, MD, PhD, Chief Scientific Officer of Applied Genomics. "Their expertise in advanced genomic and proteomic testing will provide a rigorous reference lab-based introduction of the test and broad reach in order to offer quality testing to patients nationwide."

Because Mammostrat uses traditional immunohistochemistry technology, the test is expected to be significantly less expensive than existing molecular-based, prognostic tests for breast cancer and is typically covered by insurance. Todd Maney, Ph.D., Vice President of New Product Development, MPI, stated, "Mammostrat's cost-effective, molecular-targeted analysis enables MPI to provide the test at a significant discount compared to our competitors. Moreover, test results will be available quickly -- an average of seven business days -- versus two weeks for alternative, comparable tests."

Physicians may order the Mammostrat test direct from the Molecular Profiling Institute or through their distribution partner AmeriPath by visiting http://www.molecularprofiling.com/ .

Gene Therapy Weekly, July 19, 2007

Breast Cancer Therapy; Researchers from Duke University, Duke Comprehensive Cancer Center discuss findings in breast cancer therapy

2007 JUL 19 - ( NewsRx.com) -- New investigation results, "The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers," are detailed in a study published in Breast Cancer Research and Treatment. "Estrogen receptor (ER) and/or progesterone receptor expression occurs in approximately 50% HER2 positive (HER2+) breast cancers and cross-talk between the estrogen and HER2 pathways promotes endocrine therapy resistance. The efficacy of the aromatase inhibitor letrozole in combination with trastuzumab was therefore tested in a Phase 2 study," investigators in the United States report.

"Patients with ER+ and/or PgR+ and HER2+ (IHC 2+ or 3+ or FISH+) advanced breast cancer were treated with trastuzumab plus letrozole until disease progression or unacceptable toxicity. Thirty-three patients were enrolled, of which thirty one were considered evaluable. The majority of patients (82%) had received tamoxifen and 82% had HER2 FISH+ and/or IHC 3+ tumors. Eight patients responded (1 CR and 7 PR) for an overall response rate (ORR) of 26% and a clinical benefit rate (CBR) of 52%. The median time to progression (TTP) was 5.8 months and the median duration of response (DOR) was 20.6+ months. Excluding IHC 2+, FISH-tumors, the OR was 24%, CBR 44%, TTP 5.5 months and DOR 17+ months. The combination was well tolerated with only two toxicity events requiring termination of study medication. Combined trastuzumab and letrozole treatment for patients with HER2+ and ER+ advanced breast cancer produced durable responses consistently lasting at least 1 year in one quarter of the patients. While these data are promising for a subgroup, for half the patients, trastuzumab plus letrozole was inactive," wrote P.K. Marcom and colleagues, Duke University, Duke Comprehensive Cancer Center.

The researchers concluded: "This finding demonstrates ER+ HER2+ advanced disease is heterogeneous and additional agents will be required for optimal management based on targeted therapeutics alone."

Marcom and colleagues published their study in Breast Cancer Research and Treatment (The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers. Breast Cancer Research and Treatment, 2007;102(1):43-9).

For additional information, contact P.K. Marcom, Duke Comprehensive Cancer Center, Duke University, Durham, NC USA.

The publisher of the journal Breast Cancer Research and Treatment can be contacted at: Kluwer Academic Publ, Van Godewijckstraat 30, 3311 Gz Dordrecht, Netherlands.

Gene Therapy Weekly, May 24, 2007

Breast Cancer Therapy; University of Louisville, Department of Pathology describes research in breast cancer therapy

2007 MAY 24 - ( NewsRx.com) -- Scientists discuss in "Ribozyme-targeting procathepsin D and its effect on invasion and growth of breast cancer cells: an implication in breast cancer therapy" new findings in breast cancer. According to recent research from the United States, "Procathepsin D (pCD), a zymogen of lysosomal aspartic peptidase cathepsin D, overexpression is correlated with highly invasive malignancies, including breast cancer. Recently, different studies have shown the role of secreted pCD as mitogen acting both in an autocrine and a paracrine manner."

"The aim of the present study is to examine the anti-tumor effects elicited by a decrease in the protein level of pCD by ribozyme and to explore the therapeutic potential of this specific targeting. Using the mFold program, we designed seven anti-pCD ribozymes and checked the accessibility to target pCD mRNA by RNase H cleavage experiment in a cell-free system. The sequences of the 4 most effective ribozymes were cloned and stably transfected in a highly metastatic human breast cancer cell line, MDA-MB-231, to knock down the expression of pCD. Downregulation of pCD due to ribozyme expression was observed by Western blotting and real-time RT-PCR. Stably transfected cells with anti-pCD ribozymes exhibited a significant lowering of in vitro invasion (p <0.001) and reduction in lung colonization potential in nude mice when compared to control ribozyme transfected cells. We also found that downregulation of pCD by ribozyme promotes apoptosis of MDA-MB-231 cells on serum deprivation," wrote A. Vashishta and colleagues, University of Louisville, Department of Pathology.

The researchers concluded: "These results suggest that we have generated a biologically functional ribozyme against pCD with possible therapeutic implications in breast cancer cells."

Vashishta and colleagues published their study in International Journal of Oncology (Ribozyme-targeting procathepsin D and its effect on invasion and growth of breast cancer cells: an implication in breast cancer therapy. International Journal of Oncology, 2007;30(5):1223-30).

For additional information, contact A. Vashishta, University of Louisville, Dept. of Pathology, Louisville, KY 40292 USA.

Publisher contact information for the International Journal of Oncology is: Professor D a Spandidos, 1, S Merkouri St., Editorial Office, Athens 116 35, Greece.

Keywords: United States, Louisville, Breast Cancer Therapy, Biotechnology, Breast Cancer, Breast Carcinoma, Gene Therapy, Oncology, Women's Health.

Gene Therapy Weekly, May 24, 2007

Breast Cancer; Molecules with Potential to Treat Breast Cancer Found

2007 MAY 24 - ( NewsRx.com) -- Hamilton College researchers have identified molecules that have been shown to be effective in the fight against breast cancer.

The Hamilton researchers used state-of-the-art computational techniques in a novel way to design molecules that they predicted would be effective lead compounds for breast cancer research. Scientists from the Albany Medical College subsequently synthesized the predicted molecules and showed that they were indeed potential anti-breast cancer compounds in animal systems.

A paper detailing the research, “Computational Design and Experimental Discovery of an Anti-estrogenic Peptide Derived from Alpha-Fetoprotein,” will be published in the May 16 issue of the Journal of American Chemical Society.

Winslow Professor of Chemistry George Shields and co-director of the Center for Molecular Design Karl Kirschner led the Hamilton research team with undergraduate students Katrina Lexa ‘05, Amanda Salisburg ‘08, Katherine Alser ‘09. The Albany team consisted of Leroy Joseph, Thomas Andersen, James Bennett, and Herbert Jacobsen of Albany Medical College.

Breast cancer is the most common cancer among women and tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment. Many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Consequently, there is an ongoing need for breast cancer drugs that have different molecular targets.

Previous work by the Albany Medical College researchers had shown that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat models, interacting with an unsolved receptor, while peptides smaller than eight amino acids did not.

The Hamilton researchers used advanced computational methods to predict the structure and dynamics of active peptides, leading to discovery of smaller peptides with full biological activity. The results were used to identify smaller peptides with the three dimensional structure of the larger peptides. These peptides were synthesized and shown to inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition.

This work was funded by the National Institutes of Health, the New York State Breast Cancer Research and Education fund, the Department of Defense's Breast Cancer program, and the National Science Foundation.

Founded in 1879, the Journal of the American Chemical Society is the flagship journal of the American Chemical Society and the premier medium for the worldwide publication of fundamental research in all areas of the chemical sciences. It is the most highly cited chemistry journal.

The results reported in the published article were first presented by Professor Shields at the 2006 International Symposium on Theory and Computations in Molecular and Materials Sciences, Biology and Pharmacology, on February 26, 2006, St. Simon’s Island, Ga.

The project was sponsored in part by the Department of the Army under contract # W81XWH-05-1-0441. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014 is the awarding and administering acquisition office. The content of the information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred.

It was supported by the New York State Breast Cancer Research and Education Fund through Department of Health Contract # C017922. Opinions expressed are solely those of the author and do not necessarily reflect those of the Health Research Science Board, the New York Department of Health, of the State of New York.

This material is based upon work supported by the National Science Foundation under Grant No. (CHE-0457275). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

Part of the Federal support came from the National Institutes of Health/National Cancer Institute. Federal money represents $475,870 or 82% of total project costs; non-federal funds equal $100,000 or 18% of total project costs.

Keywords: Biotechnology, Breast Cancer, Breast Carcinoma, Drug Development, Drug Resistance, Gene Therapy, Genetics, Genomics, Oncology, Peptide, Pharmaceuticals, Proteins, Proteomics, Tamoxifen, Treatment, Women's Health, Hamilton College.