© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
Calcium Supplementation and Large Bowel Polyp Risk
Data from clinical trials indicate that calcium supplements modestly decrease the risk of colorectal adenomas, but calcium's effect on different types of colorectal lesions is unclear. Wallace et al. (p. 921) compared the occurrence of different types of colorectal lesions in 930 patients who were randomly assigned to take either calcium carbonate supplements or a placebo after a previous diagnosis of colorectal adenomas. Although the data suggested that taking supplemental calcium is associated with a lower risk of developing advanced lesions compared with taking placebo, the study found weaker effects for other lesion types. The authors conclude that calcium supplementation may have greater antineoplastic effects on advanced colorectal lesions than on other types of colorectal polyps.
An editorial by Schatzkin and Peters (p. 893) reviews the proposed mechanisms by which calcium affects carcinogenesis in the large intestine, assesses the strengths and limitations of the new findings, and summarizes the current status of epidemiologic evidence on the calcium–colorectal cancer hypothesis.
Mechanism of Tamoxifen Resistance
Estrogen receptor (ER)–positive breast tumors that express high levels of the growth factor receptor HER2/neu and the ER coactivator AIB1 often develop resistance to tamoxifen. To explore the mechanism underlying this resistance, Shou et al. (p. 926) examined the activity of receptor signaling pathways in both MCF-7 breast cancer cells and MCF-7 cells engineered to overexpress HER2 (MCF-7/HER2 cells) that were treated with hormones and/or the growth factor receptor inhibitor gefitinib. MCF-7/HER2 cells treated with estrogen or tamoxifen had increased molecular cross-talk between the ER and HER2 pathways compared with parental MCF-7 cells. Tamoxifen recruited coactivator complexes to the promoter of an ER-regulated gene in MCF-7/HER2 cells and corepressor complexes in MCF-7 cells. Gefitinib pretreatment blocked tamoxifen-stimulated receptor cross-talk and prevented coactivator recruitment by tamoxifen. The authors conclude that tamoxifen resistance requires both HER2 and AIB1 and suggest that the ability of gefitinib to restore tamoxifen's antitumor effects should be studied in the clinic.
In an editorial, Hayes (p. 895) points out that tamoxifen has been of enormous benefit to many patients but also, via its estrogen agonist activity, may have harmed some. He notes that it is imperative to take advantage of advances in understanding the biology of the ER and HER2 to define future studies that may improve selection of treatment for patients with breast cancer.
Gene Polymorphisms Associated With Sex Hormones
Some studies have suggested that circulating levels of sex hormones may be associated with breast cancer risk. Dunning et al. (p. 936) examined the relationship between sex hormone levels, polymorphisms in the genes that encode the enzymes that regulate sex hormone metabolism, and breast cancer risk. They found that single nucleotide changes in the CYP19 gene were associated with estradiol levels and differences in the estradiol:testosterone ratio, and single nucleotide changes in the sex hormone–binding globulin (SHBG) gene were associated with SHBG levels and differences in the estradiol:SHBG ratio. However, the genetic mutations accounted for very little of the variance in circulating hormone levels in postmenopausal women, possibly explaining why the genes have given inconclusive results in studies of breast cancer risk.
HIF-1
and Gastric Cancer
Hypoxia-inducible factor 1 (HIF-1) mediates expression of vascular
endothelial growth factor (VEGF), which contributes to tumor angiogenesis.
Over-expression of the oxygen-regulated subunit of HIF-1, HIF-1, is
associated with tumor angiogenesis and tumor cell proliferation and invasion.
Stoeltzing et al. (p.
946) examined the effects of inhibiting HIF-1 activity on VEGF
expression in vitro and angiogenesis and human gastric cancer growth
in vivo. They found that cells that overexpressed DN-HIF1
secreted less VEGF than control cells when cultured in either nonhypoxic or
hypoxic conditions. Tumors derived from DN-HIF1–overexpressing
cells had lower final volumes, weights, and vessel areas, less tumor
endothelial cell association with pericyte-like cells, and fewer proliferating
tumor cells than tumors derived from control cells. The authors conclude that
inhibition of HIF-1 activity impairs gastric tumor growth,
angiogenesis, and vessel maturation.
Bone Sialoprotein and In Vitro Cancer Cell Invasion
Bone sialoprotein (BSP) interacts separately with matrix metalloproteinase
2 (MMP-2) and integrin v
3 and is
overexpressed in metastatic tumors. Because its role in tumor biology is
unclear, Karadag et al. (p.
956) investigated whether BSP enhanced cancer cell invasiveness by
forming a trimolecular complex with MMP-2 and integrin
v3. They found that BSP increased the
invasiveness of several types of cancer cells. Integrin binding to BSP was
required for increased invasiveness because mutating the integrin-binding site
of BSP or blocking it with specific antibodies inhibited the effect. MMP-2
activity was required because inhibiting it with chemical inhibitors or
antibodies specific to MMP-2 inhibited the effect; furthermore, addition of
BSP increased the amount of MMP-2 bound to cells in an integrin-dependent
manner. The authors conclude that invasiveness of cancer cells appears to
increase when BSP links MMP-2 to integrin
v3.
Challenges in Understanding Ductal Carcinoma In Situ
The incidence of ductal carcinoma in situ (DCIS) has increased as the use of mammography has risen. However, much remains to be learned about this noninvasive form of breast cancer. In particular, the natural history of DCIS is unclear, although women with DCIS have an increased risk of developing invasive breast cancer. In this issue, Leonard and Swain (p. 906) review current information about DCIS. They address issues and controversies in classification and diagnosis and note that an improved understanding of DCIS pathogenesis and natural history will help to clarify optimal management of the disease. Finally, they review treatment paradigms and the trials that led to them, concluding that a prospective randomized trial comparing all treatment options will be required to determine the role of adjuvant therapy in patients with good-risk DCIS.
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