Possible Linkage between the Ability to Change the Period (τ) of the Prolactin and Cortisol Rhythms in Women and Breast Cancer Risk

The 24 h profiles of plasma hormone concentrations are rhythmic. The circadian period (τ) changes in development, with seasons, and in women with different stages of the menstrual cycle. It is known that the rhythms of prolactin and cortisol are sensitive to environmental time cues, such as changes in day length and phase; however, the importance of these changes is not yet understood. This study investigates whether there is a relation between the ability of a subject to respond to external cues that are associated with seasonal changes causing alteration of the rhythm's periods in cortisol and prolactin and the epidemiologically determined susceptibility to breast cancer. It is shown that the rhythmic output pattern of prolactin and cortisol in vivo is generated by more than one oscillator and structured by more than one rhythmic component. Each cohort of American women, classified on an epidemiologic basis as high risk (HR) or low risk (LR) to develop breast cancer, expresses different rhythmic output patterns of both variables, suggesting that the genetic background as defined by the risk state is related to differences in the circadian time structure, including the ability of the subject to change the rhythm's τ. The LR cohort exhibited a statistically significant change between seasons in the rhythm's τ of both the prolactin and cortisol patterns. In contrast, the HR cohort showed no change in the rhythm's τ between seasons for prolactin and cortisol patterns. These results show that in human beings, the presence of a circannual rhythm in the circadian time structure or the ability to adapt the circadian rhythmic pattern of these variables to external cues, such as seasons, is related to the partly genetically determined risk state to develop breast cancer and may be of importance for human health.     

Circadian concepts in normal and neoplastic breast

Normal breast exhibits rhythmic properties linked to the hormonal environment of the gland in animals and humans. Breast tumors also display rhythmic properties; however, they differ from those found normally in animals and humans. Breast cancer in humans is characterized by disruption or modification of normal circadian patterns, which may be of prognostic value. The relationships between melatonin biology and breast cancer require exploration. The present work summarizes the data concerning circadian concepts in breast cancer and explores future directions in the breast cancer treatment by chronomodulation of medications during the 24h, taking advantage of the circadian time structure of breast tissue to improve the treatment outcome.     

Circadian concepts in normal and neoplastic breast

Normal breast exhibits rhythmic properties linked to the hormonal environment of the gland in animals and humans. Breast tumors also display rhythmic properties; however, they differ from those found normally in animals and humans. Breast cancer in humans is characterized by disruption or modification of normal circadian patterns, which may be of prognostic value. The relationships between melatonin biology and breast cancer require exploration. The present work summarizes the data concerning circadian concepts in breast cancer and explores future directions in the breast cancer treatment by chronomodulation of medications during the 24h, taking advantage of the circadian time structure of breast tissue to improve the treatment outcome.     

Epigenetic impact of long-term shiftwork: pilot evidence from circadian genes and whole-genome methylation analysis

Epigenetic association studies have demonstrated differential promoter methylation in the core circadian genes in breast cancer cases relative to cancer-free controls. The current pilot study aims to investigate whether epigenetic changes affecting breast cancer risk could be caused by circadian disruption through exposure to light at night. Archived DNA samples extracted from whole blood of 117 female subjects from a prospective cohort conducted in Denmark were included in this study. A polymerase chain reaction (PCR)-based method was used for detection of gene-promoter methylation, whereas genome-wide methylation analysis was performed using the Illumina Infinium Methylation Chip. Long-term shiftwork resulted in the same promoter hypomethylation of CLOCK and hypermethylation of CRY2, as was previously observed in breast cancer case-control studies. Genome-wide methylation analysis further discovered widespread methylation alterations in shiftworkers, including changes in many methylation- and cancer-relevant genes. Pathway analysis of the genes with altered methylation patterns revealed several cancer-related pathways. One of the top three networks generated was designated as "DNA replication, recombination, and repair, gene expression, behavior" with ESR1 (estrogen receptor α) featured most prominently in the network, underscoring the potential breast cancer relevance of the genes differentially methylated in long-term shiftworkers. These results, although exploratory, demonstrate the first evidence of the cancer-relevant epigenetic effects of night shiftwork, which warrant further investigation. Considering there are millions of shiftworkers worldwide, understanding the effects of this exposure may lead to novel strategies for cancer prevention and new policies regulating shiftwork.     

Ultradian, Circadian and Circannual Rhythms of Blood Glucose and Injected Insulins Documented in Six Self-Controlled Adult Diabetics

The aim of the study was to document during one to two years individual rhythmic patterns in blood glucose and injected insulin in self-controlled insulin dependent (C-peptide negative) diabetics with home blood glucose monitoring. Two females and four males with diurnal activity from 0700 to 2300 self-determined their blood glucose three to six times a day over a period of 12-27 months. Circadian and ultradian rhythms were analysed for each subject on a monthly basis to document annual rhythms. Blood glucose (BG) estimated circadian acrophases were located between 2200 and 0300 for all patients and months with few exceptions. A correlation was found between circadian mesors and amplitudes of BG in four subjects. Annual changes in BG were validated for each subject with large interindividual differences in peak times. The individual mean of injected insulin (II) varied from 40 to 80 iU with annual changes validated for each subject. A group pattern was observed with a peak time either in the autumn (four patients) or in the summer (two patients). A circadian rhythm of II was detected in almost all monthly means and for all patients. Locations of computed peak time φ of II exhibited a great stability for a given individual but large interindividual differences. Thus the rather constant φ location of BG for all subjects contrasted with interindividual differences in φ locations of II. These results suggest that rhythmic changes in BG and II should be recognized when forming a realistic strategy for timing and dosing time(s) of insulin.     

Suprachiasmatic nucleus and circadian core temperature rhythm in the rat

Core temperature was telemetered from 26 singly-housed adult male inbred Fischer rats standardized in an ambient temperature of 24 ± 1°C, in light from 0600–1800 alternating with darkness (L:D 12:12), with food and water freely available. The rats were operated upon first for bilateral electrolytic lesioning of the suprachiasmatic nucleus (SCN) or by a sham-operation, which consisted of an inserted electrode which neither penetrated into the SCN area nor was activated to produce a lesion. Next, a temperature sensor was implanted intraperitoneally. The telemetered data obtained at 10-min intervals from each rat were analyzed by the least-squares fit of certain trial periods (cosinor methods). A circadian population rhythm persisted in the SCN-lesioned rats which sustained destruction of both SCN (P < 0.01). The amplitude of the circadian temperature rhythm was attenuated(P < 0.01) and the rhythm's acrophase advanced (P < 0.05) from mid-dark to a time near the transition from light to darkness. Unilateral lesions of the suprachiasmatic nuclei altered the circadain amplitude but not the phasing.     

Ramadan fasting alters endocrine and neuroendocrine circadian patterns. Meal-time as a synchronizer in humans?

Muslims must refrain from eating, drinking, smoking, and sexual relations from sunrise to sunset during the month of Ramadan. Serum concentrations of melatonin, steroid hormones (cortisol, testosterone), pituitary hormones (prolactin, LH, FSH, GH, TSH) and thyroid hormones (free thyroxin and free triiodothyronine) were documented around the clock at six 4-hourly intervals before Ramadan began and on the twenty-third day of Ramadan (daytime fasting). Time series were analysed with repeated measures ANOVA. Statistically significant differences were found in some variables: the nocturnal peak of melatonin was diminished and may have been delayed; there was a shift in the onset of cortisol and testosterone secretion; the evening peak of prolactin was enhanced, FSH and GH rhythmic patterns were affected little or not at all by Ramadan fasting and only the serum TSH rhythm was blunted over the test time span. These data show that daytime fasting, modifications in sleep schedule and psychological and social habits during Ramadan induce changes in the rhythmic pattern of a number of hormonal variables.     

Circadian and circahemidian rhythms in plasma prolactin of the ram: seasonal changes

The existence of a circadian rhythm in plasma prolactin of the ram is controversial. Differences among authors can be related to both data sampling (e.g. interindividual changes, time of day, time of year, sampling interval among others) and statistical analyses. To test this hypothesis six adult "Préalpes du Sud" rams were studied individually during 72 hr in January (8 hr of light-16 hr of darkness), April (13L-11D), June (16L-8D) and September (13L-11D). Blood was sampled (vacutainer) from a jugular vein every hour, centrifuged and plasma samples stored at -20 degrees C until prolactin determinations (radioimmunoassay) were made. Individual time series were analysed according to three complementary methods: display of raw data (chronogram), best fitting cosine functions with different period tau (iterative cosinors) and power spectra. Seasonal changes in the 24 hr mean (peak time in June) were confirmed. A circahemidian rhythm (tau = 12 hr) and a circadian rhythm (tau = 24 hr) were validated, respectively in January and April while time series documented in June and September exhibited no rhythmic organization. It seems, therefore, that animals adjusted their rhythmic patterns of prolactin secretion to the increasing (January, April) rather than decreasing (June, September) photofraction (duration of the light span/24 hr).     

Diurnal regulation of plant growth

Life occurs in an ever-changing environment. Some of the most striking and predictable changes are the daily rhythms of light and temperature. To cope with these rhythmic changes, plants use an endogenous circadian clock to adjust their growth and physiology to anticipate daily environmental changes. Most studies of circadian functions in plants have been performed under continuous conditions. However, in the natural environment, diurnal outputs result from complex interactions of endogenous circadian rhythms and external cues. Accumulated studies using the hypocotyl as a model for plant growth have shown that both light signalling and circadian clock mutants have growth defects, suggesting strong interactions between hypocotyl elongation, light signalling and the circadian clock. Here, we review evidence suggesting that light, plant hormones and the circadian clock all interact to control diurnal patterns of plant growth.     

Alternating Reducing and Enhancing Effect of Pregnancy on Breast Cancer Risk May Reveal Periodic Phenomena which Mask Circannual Rhythms

Although a relationship between reproductive factors and breast cancer risk has been known for long, there are many contradictions between different studies, and a connection with a biological mechanism has not yet been found. Recently, new details have been revealed about different effects of pregnancy on breast cancer risk. During pregnancy breast cancer risk is strongly reduced, while inversely,some years after giving birth the risk is increased. Furthermore, risk is strongly reduced in women whose consecutive births of four or more children occur after short intervals and are terminated before the age of 30. Recently, we have postulated rhythmicity in the occurrence of breast cancer in a subgroup of young women. By analogy with circadian rhythms it may be assumed that circannual rhythms too are influenced by synchronizers and masking effects. In circadian rhythms masking may be by external or internal periodic factors, such as the sleep/wake cycle, meal timing and activity. Over the year pregnancy may be such a periodic factor, with alternation of an empty uterus and one wich gradually enlarges as a consequence of a developing fetus. A masking factor is active only as long as present. Therefore the circannual rhythmicity of breast cancer is attenuated or nullified only during pregnancy. After giving birth, the temporal deficit of the rhythmic increase of tumor growth may be restored, leading to a rebound effect expressed as an increased clinical detection of malignancy some years later. When several consecutive pregnancies occur after short intervals the masking effect continues uninterruptedly, accompanied by a strong reduced breast cancer risk. The same biological mechanism may underly the remission during pregnancy in autoimmune disorders such as rheumatoid arthritis and Graves’ disease. The immune system, crucial in autoimmune disorders, is build up of several constituents which are clearly rhythmic, e.g the lymphocytes. Masking of one or more of these rhythmicities may lead to disease attenuation, followed by relapses as soon as the masking factor has been eliminated.     

Alternating Reducing and Enhancing Effect of Pregnancy on Breast Cancer Risk May Reveal Periodic Phenomena which Mask Circannual Rhythms

Although a relationship between reproductive factors and breast cancer risk has been known for long, there are many contradictions between different studies, and a connection with a biological mechanism has not yet been found. Recently, new details have been revealed about different effects of pregnancy on breast cancer risk. During pregnancy breast cancer risk is strongly reduced, while inversely,some years after giving birth the risk is increased. Furthermore, risk is strongly reduced in women whose consecutive births of four or more children occur after short intervals and are terminated before the age of 30. Recently, we have postulated rhythmicity in the occurrence of breast cancer in a subgroup of young women. By analogy with circadian rhythms it may be assumed that circannual rhythms too are influenced by synchronizers and masking effects. In circadian rhythms masking may be by external or internal periodic factors, such as the sleep/wake cycle, meal timing and activity. Over the year pregnancy may be such a periodic factor, with alternation of an empty uterus and one wich gradually enlarges as a consequence of a developing fetus. A masking factor is active only as long as present. Therefore the circannual rhythmicity of breast cancer is attenuated or nullified only during pregnancy. After giving birth, the temporal deficit of the rhythmic increase of tumor growth may be restored, leading to a rebound effect expressed as an increased clinical detection of malignancy some years later. When several consecutive pregnancies occur after short intervals the masking effect continues uninterruptedly, accompanied by a strong reduced breast cancer risk. The same biological mechanism may underly the remission during pregnancy in autoimmune disorders such as rheumatoid arthritis and Graves' disease. The immune system, crucial in autoimmune disorders, is build up of several constituents which are clearly rhythmic, e.g the lymphocytes. Masking of one or more of these rhythmicities may lead to disease attenuation, followed by relapses as soon as the masking factor has been eliminated.     

Neuropeptide chronomics in clinically healthy young adults: circaoctohoran and circadian patterns

Endothelin-1 (ET-1) undergoes an about 8-h (circaoctohoran) rather than a circadian variation in clinical health. Herein, 24 h plasma concentrations of vasoactive intestinal peptide (VIP), substance P (SP), neuropeptide Y (NpY), and cortisol used as reference, were obtained from 20 healthy young adults starting at 07:00 or 19:00 h. Like ET-1, SP and NpY undergo a circaoctohoran variation, whereas VIP is circadian rhythmic, peaking during the night, some 8 h prior to the circadian acrophase of cortisol. Maps of circadian and extra-circadian patterns may serve for screening, diagnosis and a better understanding of mechanisms underlying the etiology of various diseases.     

Birth weight, breast cancer and the potential mediating hormonal environment

Background

Previous studies have shown that woman’s risk of breast cancer in later life is associated with her infants birth weights. The objective of this study was to determine if this association is independent of breast cancer risk factors, mother’s own birth weight and to evaluate association between infants birth weight and hormonal environment during pregnancy. Independent association would have implications for understanding the mechanism, but also for prediction and prevention of breast cancer.

Methods and Findings

Risk of breast cancer in relation to a first infant’s birth weight, mother’s own birth weight and breast cancer risk factors were evaluated in a prospective cohort of 410 women in the Framingham Study. Serum concentrations of estriol (E3), anti-estrogen alpha-fetoprotein (AFP), and pregnancy-associated plasma protein-A (PAPP-A) were measured in 23,824 pregnant women from a separate prospective cohort, the FASTER trial. During follow-up (median, 14 years) 31 women (7.6 %) were diagnosed with breast cancer. Women with large birth weight infants (in the top quintile) had a higher breast cancer risk compared to other women (hazard ratio (HR), 2.5; 95% confidence interval (CI), 1.2–5.2; P = 0.012). The finding was not affected by adjustment for birth weight of the mother and traditional breast cancer risk factors (adjusted HR, 2.5; 95% CI, 1.2–5.6; P = 0.021). An infant’s birth weight had a strong positive relationship with the mother’s serum E3/AFP ratio and PAPP-A concentration during pregnancy. Adjustment for breast cancer risk factors did not have a material effect on these relationships.

Conclusions

Giving birth to an infant with high birth weight was associated with increased breast cancer risk in later life, independently of mother’s own birth weight and breast cancer risk factors and was also associated with a hormonal environment during pregnancy favoring future breast cancer development and progression.     

Working against our endogenous circadian clock: Breast cancer and electric lighting in the modern world

Breast cancer incidence increases rapidly as societies industrialize. Many changes occur during the industrialization process, one of which is a dramatic alteration in the lighted environment from a sun-based system to an electricity-based system. Increasingly, the natural dark period at night is being seriously eroded for the bulk of humanity. Based on the fact that light during the night can suppress melatonin, and also disrupt the circadian rhythm, it was proposed in 1987 that increasing use of electricity to light the night accounts in part for the rising risk of breast cancer globally. Predictions from the theory include: non-day shift work increases risk, blindness lowers risk, long sleep duration lowers risk, and population level community nighttime light level co-distributes with breast cancer incidence. Thus far, studies of these predictions are consistent in support of the theory. A new avenue of research has been on function of circadian genes and whether these are related to breast cancer risk. In particular, a length variant of Per3 (5-VNTR) has been associated with increased risk in young women, and this same 5-VNTR variant has also been found to predict morning diurnal type and shorter sleep duration compared to the 4-VNTR variant. An important question is how an effect of light-at-night (LAN) exposure on breast cancer risk might be modified by polymorphisms and/or epigenetic alterations in the circadian genes, and conversely whether light-at-night exposure (e.g., shift work) can induce deleterious epigenetic changes in these genes.     

HIV tropism and decreased risk of breast cancer

Background

During the first two decades of the U.S. AIDS epidemic, and unlike some malignancies, breast cancer risk was significantly lower for women with human immunodeficiency virus (HIV) infection compared to the general population. This deficit in HIV-associated breast cancer could not be attributed to differences in survival, immune deficiency, childbearing or other breast cancer risk factors. HIV infects mononuclear immune cells by binding to the CD4 molecule and to CCR5 or CXCR4 chemokine coreceptors. Neoplastic breast cells commonly express CXCR4 but not CCR5. In vitro, binding HIV envelope protein to CXCR4 has been shown to induce apoptosis of neoplastic breast cells. Based on these observations, we hypothesized that breast cancer risk would be lower among women with CXCR4-tropic HIV infection.

Methods and Findings

We conducted a breast cancer nested case-control study among women who participated in the WIHS and HERS HIV cohort studies with longitudinally collected risk factor data and plasma. Cases were HIV-infected women (mean age 46 years) who had stored plasma collected within 24 months of breast cancer diagnosis and an HIV viral load ≥500 copies/mL. Three HIV-infected control women, without breast cancer, were matched to each case based on age and plasma collection date. CXCR4-tropism was determined by a phenotypic tropism assay. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were estimated by exact conditional logistic regression. Two (9%) of 23 breast cancer cases had CXCR4-tropic HIV, compared to 19 (28%) of 69 matched controls. Breast cancer risk was significantly and independently reduced with CXCR4 tropism (adjusted odds ratio, 0.10, 95% CI 0.002–0.84) and with menopause (adjusted odds ratio, 0.08, 95% CI 0.001–0.83). Adjustment for CD4⁺ cell count, HIV viral load, and use of antiretroviral therapy did not attenuate the association between infection with CXCR4-tropic HIV and breast cancer.

Conclusions

Low breast cancer risk with HIV is specifically linked to CXCR4-using variants of HIV. These variants are thought to exclusively bind to and signal through a receptor that is commonly expressed on hyperplastic and neoplastic breast duct cells. Additional studies are needed to confirm these observations and to understand how CXCR4 might reduce breast cancer risk.     

Involvement of glial cells in rhythmic size changes in neurons of the housefly's visual system

In the housefly's first optic neuropile, or lamina, the axons of two classes of monopolar cell interneurons, L1 and L2, exhibit a daily rhythm of size changes: swelling during the day, and shrinking by night. At least for the L2 cells this rhythm is circadian. Moreover, epithelial glial cells that enwrap each lamina cartridge, its monopolar cell axons, and their surrounding crown of input photoreceptor terminals also change size, but in the opposite direction to the changes in L1 and L2-swelling by night and shrinking by day. The rhythmic changes in glia indicate the possible involvement of these cells in the lamina's circadian system. To examine their role in regulating the rhythmic changes of L1 and L2's axon sizes we have injected three chemicals into the haemolymph of the fly's head: fluorocitrate (FL) and iodoacetate (IAA), which affect the metabolism of glial cells, and octanol (OC), which closes gap junction channels. All chemicals exerted an effect on L1 and L2, which depended on the time of injection, the drug concentration, and the postinjection times at which we examined the fly's brains. Moreover, day/night changes in the axon sizes of L1 and L2 were increased in FL- and IAA-treated flies, indicating that glial cells may normally inhibit these changes by regulating the sizes of L1 and L2's axons during the day and night. In turn, lack of a day/night rhythm in L1 and L2 after OC injections shows that the rhythm's persistence depends on communication between the lamina cells through gap junction channels.     

Systems Biology and Genomics of Breast Cancer

It is now accepted that breast cancer is not a single disease, but instead it is composed of a spectrum of tumor subtypes with distinct cellular origins, somatic changes, and etiologies. Gene expression profiling using DNA microarrays has contributed significantly to our understanding of the molecular heterogeneity of breast tumor formation, progression, and recurrence. For example, at least two clinical diagnostic assays exist (i.e., OncotypeDX RS and Mammaprint®) that are able to predict outcome in patients using patterns of gene expression and predetermined mathematical algorithms. In addition, a new molecular taxonomy based upon the inherent, or “intrinsic,” biology of breast tumors has been developed; this taxonomy is called the “intrinsic subtypes of breast cancer,” which now identifies five distinct tumor types and a normal breast-like group. Importantly, the intrinsic subtypes of breast cancer predict patient relapse, overall survival, and response to endocrine and chemotherapy regimens. Thus, most of the clinical behavior of a breast tumor is already written in its subtype profile. Here, we describe the discovery and basic biology of the intrinsic subtypes of breast cancer, and detail how this interacts with underlying genetic alternations, response to therapy, and the metastatic process.     

Circadian rhythms of 11-hydroxycorticosteroid excretion in rats administered cortisol at different times of the day

Male Wistar rats housed under the conditions of 12L : 12D, 24 +/- 1 degree C and free access to food and water received isotonic sodium chloride solution or cortisol in doses of 2 and 4 mg/kg, respectively. Daily stress or cortisol injections in the morning or evening are the synchronizers of 11-hydroxycorticosteroid excretion rhythm. Morning stress leads to the increase of the 12-hour rhythm. On the contrary, evening stress or cortisol administration during maximal endogenous secretion of corticosteroids are associated with the elevation of circadian periodicity. Exogenic changes in the rhythmic organization of the hypothalamo-hypophyseal-adrenocortical system are followed by activation of adaptive processes involved in the normalization of the initially modified glucocorticoid rhythm.