Editor’s note: Science Scan is a roundup of recently published biotechnology-relevant research.
A white pill, tamoxifen by name, is credited with a major role in the decline of breast cancer deaths during the past decade. Conversely, the same drug heightens the risk of endometrial carcinoma (cancer of the uterus). What accounts for this white-hat/black-hat rep?
“Tamoxifen is a very important drug used in the treatment and prevention of estrogen-responsive breast cancer,” observed medical oncologist Myles Brown at the Harvard-affiliated Dana-Farber Cancer Institute in Boston. “While it is a very good chemotherapeutic,” he continued, “tamoxifen has this unwanted side effect its ability, like that of estrogen, to induce uterine cancers. That has caused some women not to want to take tamoxifen. Our work helps explain how this happens.” Brown reports his seemingly contrarian work in the current issue of Science, dated March 29, 2002. Its title: “Molecular determinants for the tissue specificity of SERMs.”
“About eight years ago,” Brown told BioWorld Today, “we first proposed that other molecules would be involved in the function of the estrogen receptor, and other steroid hormone receptors brought to the genes that are regulated by their various receptors. These molecules would assist in turning gene transcription on or off. What we and others have shown is that these coregulatory proteins seem to be involved in allowing cells to fine-tune their responses to different signals.
“The molecular basis for that difference,” Brown predicted, “will allow for the development of newer drugs of this class called SERMs Selective Estrogen Receptor Modulators. What we’ve helped to do in this Science paper is explain the S’ in SERM. These drugs are selective because they act like estrogen in some tissues and block estrogen action in others. We found that a set of proteins called coregulators which come in two flavors, coactivators or corepressors are differentially expressed in the uterus vs. the breast.
“The harmful estrogen-like activity of tamoxifen in the uterus requires a high level of the steroid receptor coactivator 1 (SRC-1) expression. In the uterus, tamoxifen is able to recruit coactivators to certain estrogen-responsive genes, which will lead to the growth of the uterine cells. And in the breast, that same drug recruits the corepressors to the genes responsible for growth, and prevents breast-cell proliferation.
“Tamoxifen [sold as Nolvadex by AstraZeneca plc, of London] is not the only anti-estrogen player in the game. A different type of SERM compound, raloxifene [trade-named Evista by Eli Lilly & Co., of Indianapolis], is of clinical interest because raloxifene is a SERM that is approved for treatment or prevention of osteoporosis. In the bone,” he pointed out, “estrogen has beneficial effects: it prevents bone loss and promotes bone production. That’s one of the benefits of postmenopausal women being given estrogen that is, estradiol or raloxifene. The two are different. Estradiol is a natural hormone. Raloxifene is a synthetic hormone of the SERM class. Tamoxifen both treats and prevents estrogen-responsive types of breast cancer. Raloxifene has not been studied that extensively in breast cancer yet.
“There’s a large double-blind clinical trial going on internationally at present,” Brown noted, “both in the U.S. and Canada. It’s called the STAR study, sponsored by the National Cancer Institute. STAR stands for Study of Tamoxifen And Reloxifene. Its participating women will get one or the other drug, to see whether raloxifene is as good as tamoxifen at preventing breast cancer, without the latter’s side effect of inducing increased uterine cancer risk.
“The STAR study is recruiting 16,000 women,” Brown said. “They have not finished accrual yet. Results will take quite a long time because without the endpoint data, the ability of both drugs to prevent breast cancer will be similar. And while tamoxifen does have its unwanted side effect of increasing uterine cancer, it doesn’t do it by a huge amount, so the risk associated with it is not so large. It may take several years before there are either enough breast cancers prevented or enough uterine cancers induced to see any benefit of one medication vs. the other.”
Brown made a concluding point: “I think for the biotech community, molecular understanding of the basis of SERM action should allow more rapid development of novel SERM drugs. This is already the aim of several companies in the pharmaceutical industry, and some smaller biopharma-type companies as well have programs looking for SERM types of drugs.”
Human Chromosome 22 Is Focus Of Two Studies In PNAS On Genetic Susceptibility Of Schizophrenia
A pair of papers in the Proceedings of the National Academy of Sciences (PNAS) dated March 19, 2002, casts new light on the genetic basis of schizophrenia. One study, by neuroscientists at The Rockefeller University in New York, bears the title: “Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia.” The gene PRODH2 encodes an enzyme that is widely expressed in the brain, and the DGCR6 gene may be active in early development of the nervous system. The co-authors report studying DNA from schizophrenic adults and children, their parents and matched controls. They observed variations in a genomic locus containing the two known genes. An unusual pattern of gene variation that the team discovered mimics the sequence of a neighboring non-expressed pseudogene suggesting that gene mutation may occur through gene conversion.
The second paper, by research psychiatrists at the University of Cambridge in the UK, is titled: “Gene expression analysis in schizophrenia: Reproducible upregulation of several members of the apolipoprotein L family located in a high susceptibility locus for schizophrenia on chromosome 22.” These authors examined the expression of genes from a nearby area of chromosome 22, also implicated in schizophrenia. Post-mortem analysis of brain tissue revealed a significant increase in the expression of a particular gene family in the brains of schizophrenics, compared to other psychiatric patients and controls.