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Epidemiological studies reveal link between night work and breast cancer
Newsdesk Epidemiological studies reveal link between night work and breast cancer Two epidemiological studies (J Natl Cancer Inst 2001; 93: 1557–62, 1563–68.) now strengthen the idea that nocturnal exposure to light is a risk factor for breast cancer. Bright light at night suppresses normal melatonin production which, in turn, could increase oestrogen release, stimulate the turnover of breast epithelial stem cells, and increase the risk of malignant disease. The ‘melatonin hypothesis’ was first suggested by Scott Davis (Fred Hutchinson Cancer Research Center, Seattle, WA, USA) to explain the rising cancer risk in populations with increasing use of electric power. Melatonin has since been shown to reduce the incidence of experimentally-induced breast cancer in rats and is oncostatic and cytotoxic to breast, ovarian, and bladder cancer
cell lines in vitro. Evidence that nightshift working may increase risk has also been found. Davis and colleagues have now assessed 813 night workers and 793 matched controls, and shown that the nightshift workers have a 60% increase in relative risk of breast cancer (odds ratio 1.6), rising to 100% in those who worked at least 3 nights a week, for more than 4.5 years during the previous decade. Women who did not sleep when melatonin levels would have been at their highest had a 14% increase in risk for each night per week without sleep. “Turning on the light briefly doesn’t increase the risk”, says Davis, “but prolonged wakefulness in relatively bright light seems to be an important factor”. A second study indicated a more
moderate level of risk for night workers with rotating shifts. Eva S. Schernhammer and colleagues (Harvard Medical School, Boston, Mass, USA) prospectively studied 78 562 nurses, 2411 of whom developed primary breast cancer. Workers who had been on rotating shifts for one to 29 years (57.8% of total cohort) had an 8% increase in relative risk compared with nurses on dayshifts (40.4% of total cohort). For nurses with over 30 years of night work (1.8% of total cohort), the increase was 36%. “We set up the study to look for a direct effect of night work on breast cancer”, explains Schernhammer, “and found a moderate increase in women who work at least 3 nights per month for extended periods”. Janet Stephenson
Researchers have worked out how a potent new inhibitor of BCR-ABL, called PD-173955, binds to its target. Their findings were presented at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference (Miami Beach, FL, USA; 29 October–2 November 2001). BCR-ABL is a constitutively active tyrosine kinase, resulting from the aberrant fusion of two genes, the sole mutation responsible for the initial symptoms of chronic myelogenous leukemia (CML). Patients with CML usually respond well to another BCR-ABL inhibitor, STI-571, but there is some concern about the development of resistance to this drug. Using X-ray crystallography, John Kuriyan and colleagues at the Laboratory of Molecular Biophysics, Rockefeller University and at the Memorial Sloan-Kettering Cancer Center (MSKCC) (both in New York, NY, USA) found that PD-173955 binds when the ABL kinase domain is in the open and closed conformation, whereas STI-571 binds only when the kinase is in the closed conformation.
THE LANCET Oncology Vol 2 December 2001
Courtesy of J Kuriyan
New BCR-ABL inhibitors overcome resistance to STI-571
X-ray crystallography of STI-571 (green) in complex with closed ABL kinase activation loop (pink)
“We suspect that the ability of PD-173955 to bind in both conformations is largely responsible for the increased activity compared to STI-571”, says study author Bayard Clarkson, Head of the Hematopoietic Cell Kinetics Laboratory at MSKCC. “We thought this compound would be synergistic, but to our surprise, it proved to be 15 to 20 times more active than STI-571 itself”, he adds. The initial mouse
studies indicate that the drug is tolerated at a concentration that should be active. Clarkson says he cannot predict whether the drug will overcome the resistance cancer cells develop to STI-571, but unlike STI-571, PD173955 does not form a hydrogen bond with threonine 315, one of several point mutations in ABLkinase that confers resistance to STI-571. “We are doing animal and pharmacological studies”; these are not being funded by Parke-Davis, the manufacturer of PD-173955. According to Paul Workman (Center for Cancer Therapeutics, Institute of Cancer Research, Sutton, UK) cancer cells will probably develop resistance even to the new cancer drugs being developed. “It will be important to ask whether this particular drug can overcome resistance”, he says, “but the use of X-ray crystallography to work out the atomic structure of cancer genes and cancer proteins is a powerful tool in the development of new drugs to overcome resistance”. Emma Hitt
713
For personal use. Only reproduce with permission from The Lancet Publishing Group.
cell lines in vitro. Evidence that nightshift working may increase risk has also been found. Davis and colleagues have now assessed 813 night workers and 793 matched controls, and shown that the nightshift workers have a 60% increase in relative risk of breast cancer (odds ratio 1.6), rising to 100% in those who worked at least 3 nights a week, for more than 4.5 years during the previous decade. Women who did not sleep when melatonin levels would have been at their highest had a 14% increase in risk for each night per week without sleep. “Turning on the light briefly doesn’t increase the risk”, says Davis, “but prolonged wakefulness in relatively bright light seems to be an important factor”. A second study indicated a more
moderate level of risk for night workers with rotating shifts. Eva S. Schernhammer and colleagues (Harvard Medical School, Boston, Mass, USA) prospectively studied 78 562 nurses, 2411 of whom developed primary breast cancer. Workers who had been on rotating shifts for one to 29 years (57.8% of total cohort) had an 8% increase in relative risk compared with nurses on dayshifts (40.4% of total cohort). For nurses with over 30 years of night work (1.8% of total cohort), the increase was 36%. “We set up the study to look for a direct effect of night work on breast cancer”, explains Schernhammer, “and found a moderate increase in women who work at least 3 nights per month for extended periods”. Janet Stephenson
Researchers have worked out how a potent new inhibitor of BCR-ABL, called PD-173955, binds to its target. Their findings were presented at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference (Miami Beach, FL, USA; 29 October–2 November 2001). BCR-ABL is a constitutively active tyrosine kinase, resulting from the aberrant fusion of two genes, the sole mutation responsible for the initial symptoms of chronic myelogenous leukemia (CML). Patients with CML usually respond well to another BCR-ABL inhibitor, STI-571, but there is some concern about the development of resistance to this drug. Using X-ray crystallography, John Kuriyan and colleagues at the Laboratory of Molecular Biophysics, Rockefeller University and at the Memorial Sloan-Kettering Cancer Center (MSKCC) (both in New York, NY, USA) found that PD-173955 binds when the ABL kinase domain is in the open and closed conformation, whereas STI-571 binds only when the kinase is in the closed conformation.
THE LANCET Oncology Vol 2 December 2001
Courtesy of J Kuriyan
New BCR-ABL inhibitors overcome resistance to STI-571
X-ray crystallography of STI-571 (green) in complex with closed ABL kinase activation loop (pink)
“We suspect that the ability of PD-173955 to bind in both conformations is largely responsible for the increased activity compared to STI-571”, says study author Bayard Clarkson, Head of the Hematopoietic Cell Kinetics Laboratory at MSKCC. “We thought this compound would be synergistic, but to our surprise, it proved to be 15 to 20 times more active than STI-571 itself”, he adds. The initial mouse
studies indicate that the drug is tolerated at a concentration that should be active. Clarkson says he cannot predict whether the drug will overcome the resistance cancer cells develop to STI-571, but unlike STI-571, PD173955 does not form a hydrogen bond with threonine 315, one of several point mutations in ABLkinase that confers resistance to STI-571. “We are doing animal and pharmacological studies”; these are not being funded by Parke-Davis, the manufacturer of PD-173955. According to Paul Workman (Center for Cancer Therapeutics, Institute of Cancer Research, Sutton, UK) cancer cells will probably develop resistance even to the new cancer drugs being developed. “It will be important to ask whether this particular drug can overcome resistance”, he says, “but the use of X-ray crystallography to work out the atomic structure of cancer genes and cancer proteins is a powerful tool in the development of new drugs to overcome resistance”. Emma Hitt
713
For personal use. Only reproduce with permission from The Lancet Publishing Group.