© 2005 Oxford University Press
IN THIS ISSUE
Dose-Dense Chemotherapy in Early Breast CancerTo determine whether a dose-dense chemotherapy regimen could improve outcomes in patients with early breast cancer, Venturini et al. (p. 1724) compared outcomes with the same regimen of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) given every 3 weeks (FEC21) or every 2 weeks (FEC14) in a phase III randomized trial. (Patients on FEC14 also received a granulocyte colony-stimulating factor.) After a median follow-up of 10.4 years, they found no statistically significant difference in the hazard of death or recurrence between arms. They reported that acute toxicity associated with either treatment was mild and easy to manage. Patients in the FEC14 arm had fewer dose reductions, treatment delays, or treatment discontinuations than those in the FEC21 arm. The authors conclude that their results support the long-term safety of FEC14 chemotherapy as an adjuvant treatment of breast cancer, but they note that they could not rule out a modest improvement in outcome with FEC14 therapy because their study had limited statistical power.
In an editorial, Lin et al. (p. 1712) note the lessons that can be learned from this trial. The dose-dense regimen appeared to decrease disease recurrence and to improve overall survival. They note that the difference in actual versus predicted outcome in the reference arms must be taken into account when new trials are planned, and because the data suggest a differential benefit by tumor subtype, known breast cancer biology should be considered prospectively when designing new trials.
Smad7 Expression and Metastasis Inhibition
Transforming growth factor 
(TGF-) facilitates metastasis during the advanced stages of cancer. Azuma et al. (p. 1734) used adenovirus (AdCMV)-mediated gene transfer of several natural inhibitors of TGF- superfamily signaling—Smad6, Smad7, and c-Ski—in a mouse model of breast cancer to examine the roles of TGF- superfamily signaling in tumor growth, metastasis, and survival. Mice bearing tumors derived from mouse mammary carcinoma JygMC(A) cells treated with AdCMV–Smad7 or AdCMV–c-Ski had fewer lung and liver metastases and lived longer than untreated mice. Smad7 expression in JygMC(A) cells was associated with increased expression of major components of adherens and tight junctions and decreases in the migratory and invasive abilities of the JygMC(A) cells. The authors conclude that Smad7 inhibits metastasis, possibly by regulating cell–cell adhesion.
In an editorial, Fidler (p. 1714) reviews the events that must occur for metastatic cells to produce a clinically relevant lesion, particularly the mechanisms involved in tumor cell invasion of tissues, including the loss of cell-to-cell cohesive forces that precedes increased tumor cell motility. He discusses why systemic expression of Smad7 is unlikely to reverse established metastases among patients with advancedstage disease but notes that inhibition of tumor cell motility by expression of Smad7 could break a link in the chain of events required for metastasis.
Mechanism of Estradiol-Induced Apoptosis
Although many breast cancers require estrogen to grow, estradiol can also promote apoptosis in certain cellular contexts. In particular, estradiol has been found to induce apoptosis of breast cancer cells that have developed resistance to antihormonal therapy. In this issue, Lewis et al. (p. 1746) investigated the mechanism underlying estradiol promotion of apoptosis in MCF- 7:5C cells, a breast cancer cell line that was created by long-term estrogen deprivation and is resistant to estrogen withdrawal. The authors found that estradiol induced activation of the mitochondrial (i.e., intrinsic) apoptotic pathway in MCF-7:5C cells by increasing expression of proapoptotic proteins, decreasing mitochondrial transmembrane potential, and enhancing cytochrome c release. Blockade of proapoptotic protein expression reduced estrogen induction of apoptosis. Estrogen also caused complete regression of MCF-7:5C tumors in mice. The authors suggest that these laboratory data raise the possibility that estrogen treatment may induce apoptosis and tumor regression of tumors that have developed resistance to aromatase inhibitors.
Chronic Stress and Risk of Skin Cancer
Chronic stress and exposure to UV radiation can independently suppress immunity. To determine whether the combination of chronic stress and UV exposure increases susceptibility to cancer, Saul et al. (p. 1760) used a mouse model of squamous cell carcinoma and compared the immune responses and tumor formation of mice that were UV irradiated and mice that were subjected to both UV irradiation and chronic stress. The authors found that tumors formed sooner, that the expression of type 1 cytokines and tumor CD4+ cell infiltration in the dorsal skin was lower, and that the number of tumor infiltrating and circulating CD25+ cells was higher of the UV-exposed, stressed mice than in the UV-exposed, nonstressed mice. The authors conclude that, in this mouse model, chronic stress increases susceptibility to UV-induced squamous cell carcinoma by suppressing type 1 cytokines and protective T cells and by increasing the number of suppressor T cells.
Dairy and Calcium Intakes and Prostate Cancer Risk
To examine associations between calcium and dairy product intakes and the risk of prostate cancer, Gao et al. (p. 1768) conducted a meta-analysis of 12 publications (from 10 prospective studies) published between 1966 and May 2005. They found that men with the highest intakes of dairy products and calcium were more likely to develop prostate cancer than men with the lowest intakes. Dose–response analyses suggested that dairy product and calcium intakes were each positively associated with the risk of prostate cancer. The authors conclude that high intakes of dairy products and calcium may be associated with a small increased risk of prostate cancer.
Tlr4 in Chronic Lung Inflammation and Tumorigenesis
When activated by extracellular signals, Toll-like receptors (TLRs) stimulate the innate immune system to initiate the inflammatory response. Lung diseases that are characterized by chronic lung inflammation increase the risk of lung cancer. To determine whether a particular TLR, Tlr4, is involved in chronic lung inflammation, Bauer et al. (p. 1778) compared chemically-induced lung inflammation and tumor formation in mice expressing either functional or mutated Tlr4. The authors found that the lungs of mice with functional Tlr4 had less inflammation and fewer tumors than the lungs of mice with mutated Tlr4. They conclude that Tlr4 may have a modulatory role in chronic lung inflammation and tumorigenesis.
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