Night Shift Work and the Risk of Breast Cancer

US Pharm. 2014;39(5)(Specialty&Oncology suppl):9-11.

ABSTRACT: Excluding skin cancer, breast cancer is the most common form of cancer in women. There are multiple physiological, genetic, and environmental factors known to increase a woman’s risk of breast cancer. Night shift work has been proposed by the International Agency for Research on Cancer as a risk factor for breast cancer, and several studies have been done to analyze this risk. Studies looking both prospectively and retrospectively have considered frequency and duration of shift work and other physiological factors in breast cancer development in women. These studies have found conflicting evidence on the impact of night shift work as a risk factor for breast cancer.

Breast cancer is the second most common form of cancer in the United States, and the most common type of cancer in women (excluding certain types of skin cancer), with an incidence of about 120 cases per 100,000 persons.¹ In 2010 alone, 40,996 women died of breast cancer.¹

Currently, age represents the greatest risk factor for the development of breast cancer in women.^1-3 There are a multitude of genetic mutations that predispose patients to breast cancer.³ Environmental factors that can increase female breast cancer risk include hormone replacement therapy, smoking, diet, and alcohol consump-tion.^2-5 Night shift work is another proposed epidemiologic factor.

Pathophysiology

Sleep-Wake Cycle: Due to atypical work times, patients who work night shifts often sleep less, and when they do sleep, quality is reduced. It is likely that disturbances in the circadian rhythm and the sleep-wake cycle contribute to increased sleepiness and the health problems that are associated with shift work.^6-8 In those who are on typical schedules and sleep at night, there is a balance between the sleep-wake cycle and the circadian rhythm, allowing most people 8 hours of uninterrupted sleep each night. Patients who sleep during the day experience an imbalance between these two processes and sleep an average of 5.5 hours or less each day.⁷ This results not only in increases in fatigue but also in changes in hormonal rhythms over time.

Cortisol and Melatonin: Cortisol and melatonin are two hormones that contribute largely to the sleep-wake cycle. In people who sleep during the night, cortisol peaks during the day and is at its minimal levels at night-time, whereas melatonin levels are the opposite.⁹ Despite significant changes in sleep schedules in people who sleep during the day, cortisol and melatonin cycles continue to peak and trough the same way they would in typical sleepers.^10,11 As a response to elevated levels of melatonin at night when a shift worker needs to be awake, the body tries to suppress the release of melatonin, resulting in decreases in overall levels.⁷

Several studies have looked at the relationship between abnormal cortisol levels and breast cancer. A study completed by van der Pompe et al compared cortisol levels in women with breast cancer to matched controls without breast cancer.¹² The authors saw significant elevations in cortisol levels in women with a breast cancer diagnosis in comparison to the controls. A second study by Sephton et al saw that breast cancer patients with abnormal circadian rhythm and cortisol levels had a significantly increased mortality than those with uninterrupted circadian rhythms.¹³

There are some theories that state that decreases in melatonin can result in increased cancer risk, specifically breast cancer.⁶ Mammary gland growth is partially regulated by release of hormones from the pituitary. Release of melatonin down-regulates the pituitary, decreasing the release of reproductive hormones; therefore, a decrease in melatonin can possibly cause an increase in hormone levels. Melatonin is also thought to act directly on tumor cells, by helping to decrease the rate at which they multiply and through its antioxidant effects.

Epidemiologic Studies

Night Work and Breast Cancer Risk: Several observational studies have attempted to identify a link between night shift work and breast cancer. TABLE 1 summarizes these trials.^14-19

The study completed by Hansen and Stevens looked at women who worked various late-night and overnight shifts, analyzing cancer risk based on women who worked permanent overnights versus rotating daytime and nighttime shifts.¹⁴ The authors have proposed that women who work permanent overnight shifts may eventually have a reduced risk of breast cancer because the circadian rhythm and sleep-wake cycles can better adjust to the night environment. Menegaux et al backed this theory further when they found that the odds ratio (OR) for women who worked at night >3 days per week was significant (1.43 [CI 1.01-2.03]).¹⁷ In women who worked night shifts at least 3 times per week, there was no significant association between night work and breast cancer (OR 1.14 [CI 0.82-1.59]). An increase in the risk of breast cancer due to menopausal hormonal therapy was observed, which was consistent with previous literature. However, even when adjusted for the use of hormonal therapy, breast cancer remained significantly more prevalent in patients who worked night shifts than those who did not.¹⁷

The study done by Pesch et al also found an increased risk of breast cancer in younger women exposed to night shift work, an idea that was backed by the results of Menegaux’s study.^17,18 The authors proposed that this could be because mammary gland cells do not terminally differentiate until after the first full-term pregnancy.¹⁸ The results of these studies may indicate that circadian disruption has greater carcinogenic potential in younger women whose mammary gland cells are not fully differentiated.

Melatonin and Breast Cancer Risk: Women’s reproductive hormones, including endogenous estrogen and progesterone, can increase the risk for breast cancer because of the stimulation of cell growth mediated by these hormones.^6,20 Normal circadian rhythm is a key factor in the regulation of these reproductive hormones, so a disruption of the sleep-wake cycle can affect the levels of estrogen and progesterone in a woman’s body.²¹ Melatonin levels are a commonly used biomarker in determining the degree of circadian deregulation because the levels are not easily affected by environmental changes, whereas other biomarkers, such as body temperature, blood pressure, and heart rate, can be.

Studies indicate that decreased levels of melatonin can result in increased levels of circulating hormones due to a negative feedback mechanism associated with the hypothalamic-pituitary-gonadal access.^21-23 Because of this, in addition to its direct oncostatic properties, melatonin also inhibits cancer through its regulation of hormone levels. If melatonin levels are altered in shift workers, these factors could be associated with breast cancer risk and working overnight.²¹

Melatonin supplementation is used to help people who work night shifts synchronize their sleep schedules, but evidence regarding supplementation to decrease breast cancer risk is lacking. Schernhammer et al reported no decrease in the breast cancer biomarkers insulin-like growth factor I (IGF-1), insulin-like growth factor–binding protein 3 (IGFBP-3), or estradiol in postmenopausal breast cancer survivors.²⁴ This study, however, did not include women who worked at night and did not measure changes in cortisol. Further research is needed to assess the safety of long-term melatonin use and its benefit as a preventive therapy in women who work night shifts.

Conclusion

Overall, it appears there could be a correlation between night shift work and breast cancer. In 2007, the International Agency for Research on Cancer stated that night shift work is “probably carcinogenic to humans.”²⁵ Several studies have found an increased risk of breast cancer in women who work overnights in a variety of different fields.^14-17 Menegaux et al found that the greatest risk is associated with women who worked night shifts for at least 4 years prior to their first pregnancy.¹⁷ There have also been some conflicting studies that did not find any increased cancer risk in women working the night shift (TABLE 1).^18,19

Further research can be done looking at the relation between frequency and duration of shift work and melatonin levels over time, the age at which women are exposed to night shift work, and any possible correlation between how low melatonin levels trough and breast cancer risk. Considering the research analyzed and that some studies have not found an increased risk of breast cancer in women who work overnights, further research is needed to determine if night shift work is carcinogenic to women.

REFERENCES

1. CDC. Breast cancer. www.cdc.gov/cancer/breast/statistics/. Accessed April 8, 2014.
2. Chun J, Pocock B, Joseph KA, et al. Breast cancer risk factors in younger and older women. Ann Surg Oncol. 2009;16:96-99.
3. National Cancer Institute. Genetics of breast and ovarian cancer (PDQ). www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/healthprofessional/page1#section_15. Accessed October 6, 2013.
4. Youlden DR, Cramb SM, Dunn NA, et al. The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol. 2012;36:237-248.
5. Porter P. Westernizing women’s risks? Breast cancer in lower income countries. N Engl J Med. 2008;358:213-216.
6. Knutsson A. Health disorders of shift workers. Occup Med (Lond). 2003;53:103-108.
7. Boivin DB, Tremblay GM, James FO. Working on atypical schedules. Sleep Med. 2007;8:578-589.
8. Postnove S, Robinson PA, Postnov DD. Adaptation to shift work: physiologically based modeling of the effects of lighting and shifts’ start time. PLoS One. 2013;8:e53379.
9. Boivin DB, James FO. Light treatment and circadian adaptation to shift work. Ind Health. 2005;43:34-48.
10. Weibel L, Brandenberger G. Disturbances in hormonal profiles of night workers during their usual sleep and work times. J Biol Rhythms. 1998;13:202-208.
11. Cos S, Sanchez-Barcelo EJ. Melatonin and mammary pathological growth. Front Neuroendocrinol. 2000;21:133-170.
12. van der Pompe G, Antoni MH, Heijnen CJ. Elevated basal cortisol levels and attenuated ACTH and cortisol responses to a behavioral challenge in women with metastatic breast cancer. Psychoneuroendocrinology. 1996;21:361-374.
13. Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst. 2000;92:994-1000.
14. Hansen J, Stevens RG. Case-control study of shift-work and breast cancer risk in Danish nurses: impact of shift systems. Eur J Cancer. 2012;48:1722-1729.
15. Knutsson A, Alfredsson L, Karlsson B, et al. Breast cancer among shift workers: results of the WOLF longitudinal cohort study. Scand J Work Environ Health. 2013;39:170-177.
16. Megdal SP, Kroenke CH, Laden F, et al. Night work and breast cancer risk: a systematic review and meta-analysis. Eur J Cancer. 2005;41:2023-2032.
17. Menegaux F, Truong T, Anger A, et al. Night shift work and breast cancer: a population-based case-control study in France (the CECILE study). Int J Cancer. 2013;132:924-931.
18. Pesch B, Harth V, Rabstein S, et al. Night work and breast cancer—results from the GENICA study. Scand J Work Environ Health. 2010;36:134-141.
19. Pronk A, Ji BT, Shu XO, et al. Night-shift work and breast cancer risk in a cohort of Chinese women. Am J Epidemiol. 2010;171:953-959.
20. National Cancer Institute. Reproductive history and breast cancer. www.cancer.gov/cancertopics/factsheet/Risk/reproductive-history. Accessed November 27, 2013.\
21. Mirick DK, Davis S. Melatonin and a biomarker for circadian dysregulation. Cancer Epidemiol Biomarkers Prev. 2008;17:3306-3313.
22. Yie SM, Brown GM, Liu GY, et al. Melatonin and steroids in human pre-ovulatory follicular fluid: seasonal variations and granulosa cell steroid production. Hum Reprod. 1995;10:50-55.
23. Penny R, Stanczyk F, Goebelsmann U. Melatonin: data consistent with a role in controlling ovarian function. J Endocrinol Invest. 1987;10:499-505.
24. Schernhammer ES, Giobbie-Hurder A, Gantman K, et al. A randomized controlled trial of oral melatonin supplementation and breast cancer biomarkers. Cancer Causes Control. 2012;23:609-616.
25. International Agency for Research on Cancer. IARC Monographs Programme finds cancer hazards associated with shiftwork, painting, and firefighting. www.iarc.fr/en/media-centre/pr/2007/pr180.html. Accessed November 29, 2013.

To comment on this article, contact rdavidson@uspharmacist.com.