Estrogen withdrawal,increased breast cancer risk and the KRAS-variant

The KRAS-variant is a biologically functional, microRNA binding site variant, which predicts increased cancer risk especially for women. Because external exposures, such as chemotherapy, differentially impact the effect of this mutation, we evaluated the association of estrogen exposures, breast cancer (BC) risk and tumor biology in women with the KRAS-variant. Women with BC (n = 1712), the subset with the KRAS-variant (n = 286) and KRAS-variant unaffected controls (n = 80) were evaluated, and hormonal exposures, KRAS-variant status, and pathology were compared. The impact of estrogen withdrawal on transformation of isogenic normal breast cell lines with or without the KRAS-variant was studied. Finally, the association and presentation characteristics of the KRAS-variant and multiple primary breast cancer (MPBC) were evaluated. KRAS-variant BC patients were more likely to have ovarian removal pre-BC diagnosis than non-variant BC patients (p = 0.033). In addition, KRAS-variant BC patients also appeared to have a lower estrogen state than KRAS-variant unaffected controls, with a lower BMI (P < 0.001). Finally, hormone replacement therapy (HRT) discontinuation in KRAS-variant patients was associated with a diagnosis of triple negative BC (P < 0.001). Biologically confirming our clinical findings, acute estrogen withdrawal led to oncogenic transformation in KRAS-variant positive isogenic cell lines. Finally, KRAS-variant BC patients had greater than an 11-fold increased risk of presenting with MPBC compared to non-variant patients (45.39% vs 6.78%, OR 11.44 [3.42–37.87], P < 0.001). Thus, estrogen withdrawal and a low estrogen state appear to increase BC risk and to predict aggressive tumor biology in women with the KRAS-variant, who are also significantly more likely to present with multiple primary breast cancer.     

Endogenous oestrogens and breast cancer risk in premenopausal and postmenopausal women

Breast cancer risk is strongly related to several reproductive and hormonal factors, but the nature of the effects of endogenous oestrogens has been difficult to establish. Data are now available from several large prospective studies with biobanks of stored serum, enabling better characterization of the associations of endogenous oestrogens, and other endogenous hormones, with breast cancer risk. In postmenopausal women, relatively high serum concentrations of oestradiol are associated with a more than twofold increase in the risk for breast cancer, and this probably explains the increase in risk in obese postmenopausal women. In premenopausal women the data available on oestrogens are more limited and difficult to interpret due to the large variations in endogenous oestrogens during the menstrual cycle, but are compatible with a positive association between oestradiol and breast cancer risk. There is also evidence that breast cancer risk is positively associated with androgens, prolactin and insulin-like growth factor-I. Further data are required, with better assays and repeat measures, to provide more accurate estimates of risk and to clarify the role of oestrogens in premenopausal women and the roles of other endogenous hormones.     

Recreational physical activity and risk of papillary thyroid cancer among women in the California Teachers Study

Purpose: Little is known about the relationship between physical activity and thyroid cancer risk, and few cohort data on this association exist. Thus, the present study aimed to prospectively examine long-term activity and risk of papillary thyroid cancer among women. Methods: 116,939 women in the California Teachers Study, aged 22–79 years with no history of thyroid cancer at cohort entry, were followed from 1995–1996 through 2009; 275 were diagnosed with invasive papillary thyroid cancer. Cox proportional-hazards regression provided relative risk (RR) estimates and 95% confidence intervals (CI) for associations between thyroid cancer and combined strenuous and moderate recreational physical activity both in the long-term (high school through age 54 years or current age if younger than 54 years) and recently (during the three years prior to joining the cohort). Results: Overall, women whose long-term recreational physical activity averaged at least 5.5 MET-hours/week (i.e. were active) had a non-significant 23% lower risk of papillary thyroid cancer than inactive women (RR = 0.77, 95% CI: 0.57, 1.04). RR estimates were stronger among normal weight or underweight women (body mass index, BMI < 25.0 kg/m², trend p = 0.03) than among overweight or obese women (trend p = 0.35; homogeneity-of-trends p = 0.03). A similar pattern of risk was observed for recent activity (BMI < 25 kg/m², trend p = 0.11; BMI ≥ 25 kg/m², trend p = 0.16; homogeneity-of-trends p = 0.04). Associations for long-term activity did not appear to be driven by activity in any particular life period (e.g. youth, adulthood). Conclusions: Long-term physical activity may reduce papillary thyroid cancer risk among normal weight and underweight women.     

Rest-activity rhythm in breast cancer survivors: an update based on non-parametric indices

ABSTRACT

Recently we evaluated by actigraphy the rest-activity circadian rhythm (RAR) in breast cancer (BC) survivors at 5 years from primary diagnosis, as well as in a control group with similar age and body mass index (BMI). RAR, analyzed by Cosinor method, resulted significantly different in BC survivors compared to healthy subjects: BC survivors showed lower values of MESOR and Amplitude (A), while acrophase (φ) was similar in the two groups.

Now, using non-parametric methods we have detected Interdaily Stability (IS), Intradaily Variability (IV), nocturnal activity (L5), and daily activity (M10) on the same sample of previous study: 15 BC survivors at 5 years from the primary diagnosis (mean age = 56.7 ± 6.6 yrs; mean BMI = 24.5 ± 3.8 Kg/m²) and 13 healthy controls (mean age = 54.4 ± 7.2 yrs; mean BMI = 25.2 ± 2.8 Kg/m²).

The non-parametric indices showed that in BC-group IV was significantly higher than in Ctrl-group (0.86 vs. 0.65 a.u. in BC and Ctrl, respectively; p <.01), while L5 (11.27 vs. 34.41 a.c. in BC and Ctrl, respectively; p <.0001) and M10 (326.82 vs. 428.07 a.c. in BC and Ctrl, respectively; p <.01) were significantly lower compared to Ctrl-group.

The data suggest that BC patients need constant clinical assessment of RAR characteristics along the years following the primary diagnosis. The analysis of RAR in all its components, parametric and non-parametric, is important to detect alterations in the sleep-wake cycle and can be useful for developing new strategies for health protection, such as structured and tailored physical activity programs, to improve circadian activity level in order to raise the quality of life in BC survivors.     

An examination of the relationship between sunlight exposure and hot flush in working women

ABSTRACT

We examined whether sunlight affects hot flushes in working menopausal women and explored effect modification by shift work and season. In this prospective cohort study, daily hot flush score (outcome) was measured by the 7-day North Central Cancer Treatment Group Daily Vasomotor Symptoms Diary. Daily duration of sunlight (≥2000 lux) was recorded by the HOBO MX2202 pendant. Both variables were measured in two 7-day data collection phases. T0 data were collected during the Australian Summer (December 2017, January and February 2018); and T1 data were collected in the Australian winter (June, July and August 2018). Linear mixed effects model was used. Shift work and season were both confounders and effect modifiers. To detect a median effect size of R² = 0.2, 34 women were required to achieve an effective sample size of 41. A total of 49 menopausal women were recruited, 11 shift and 38 day workers. Some 13 women had various missing observations. For shift workers, an hour increase in sunlight exposure was associated with a 1.4-point reduction in hot flush score (p = .016). This relationship was not significant for day workers (p = .185). The finding of this study suggests increased sunlight exposure might improve hot flushes in menopausal shift workers who are moderately bothered by hot flushes, but probably not in day workers. The possible role of shift-work associated circadian disruption on estrogen level in regard to elevated intensity and frequency of hot flush in menopausal women is discussed.     

Possible linkage between the ability to change the period (tau) 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.     

A different methylation profile of circadian genes promoter in breast cancer patients according to clinicopathological features

ABSTRACT

One of the supposed mechanisms that may lead to breast cancer (BC) is an alteration of circadian gene expression and DNA methylation. We undertook an integrated approach to identify methylation pattern of core circadian promoter regions in BC patients with regard to clinical features. We performed a quantitative methylation-specific real-time PCR analysis of a promoter methylation profile in 107 breast tumor and matched non-tumor tissues. A panel of circadian genes CLOCK, BMAL1, PERIOD (PER1, 2, 3), CRYPTOCHROME (CRY1, 2) and TIMELESS as well as their association with clinicopathological characteristics were included in the analysis. Three out of the eight analyzed genes exhibited marked hypermethylation (PER1, 2, 3), whereas CLOCK, BMAL1, CRY2 showed significantly lower promoter CpG methylation in the BC tissues when compared to the non-tumor tissues. Among variously methylated genes we found an association between the elevated methylation level of PERs promoter region and molecular subtypes, histological subtypes and tumor grading of BC. Methylation status may be associated with a gene expression level of circadian genes in BC patients. An aberrant methylation pattern in circadian genes in BC may provide information that could be used as novel biomarkers in clinics and molecular epidemiology as well as play an important role in BC etiology.     

Estrogen, alcohol and breast cancer risk

Estrogen replacement has been used for many years to reverse the hypoestrogenic symptoms of menopause and prevent osteoporosis. Studies have found that estrogen replacement also decreases cardiovascular risk. In addition, social use of alcohol has been found to decrease cardiovascular risk. Therefore, both estrogen replacement therapy and alcohol use have been proposed to have cardiovascular benefits, and are often used in combination. Epidemiologic evidence indicates that estrogen replacement therapy after menopause increases breast cancer risk. Regular alcohol consumption is also associated with increase in risk. However, interactions between the two are poorly understood. In addition, if alcohol alters circulating estrogen levels in estrogen users, this may have implications in terms of altering the risks:benefit ratio of estrogen replacement in an undesirable direction. For example, there are data suggesting that the use of both alcohol and estrogen may increase breast cancer risk more than the use of either one alone. Data support both acute and chronic effects of alcohol in raising circulating estrogen levels in premenopausal women on no hormonal medications. In postmenopausal women studies focusing on acute effects of alcohol on estrogen metabolism indicate that alcohol has a much more pronounced effect in women using estrogen replacement than in those who do not. Studies evaluating chronic effects of alcohol ingestion on circulating estrogens in postmenopausal women are needed.     

Body composition and breast cancer in postmenopausal women: a Danish prospective cohort study

Objective: To assess the importance of body fat mass (BFM) and fat free mass (FFM) for the established positive association between BMI and breast cancer among post‐menopausal women. Research Methods and Procedures: A prospective cohort of 23,788 postmenopausal women included in the Danish study Diet, Cancer, and Health during 1993 to 1997 was linked to the Danish Cancer Registry to identify all cases of breast cancer occurring during 1993 to 2002. Breast cancer incidence rate ratios for anthropometric measurements with adjustment for known risk factors for breast cancer were calculated by Cox regression analyses. Results: Among the most commonly used anthropometric measurements, BMI was positively associated with breast cancer among never users of hormone replacement therapy (HRT). By splitting BMI into two indices, BFM index and FFM index, we found that the incidence rate ratio with each 1 kg/m² among never users of HRT was 0.98 (95% confidence interval, 0.93 to 1.03) for BFM index and 1.12 (95% confidence interval, 1.00 to 1.26) for FFM index after mutual adjustment. Discussion: The finding for BMI was in accordance with previous findings. Our results indicate that the FFM component of BMI may play a role for development of breast cancer among never users of HRT.     

Physical activity and the risk of breast cancer among Nigerian women

BackgroundAlthough physical activity has been associated with a reduced risk of breast cancer risk in high income countries (HIC), its role has not been widely studied in sub-Saharan Africa. Our aim was to investigate the association between physical activity (PA) and the risk of breast cancer in Nigeria.MethodsWe conducted a hospital-based case-control study involving participants from five hospitals in Lagos and Abuja. Women were interviewed in-person between October 2016 and May 2017 using a semi-structured questionnaire. Total PA was estimated by summing occupational, household, transport and leisure PA scores. PA was summarised as metabolic equivalents (MET) hours per week (MET-hr/wk). The putative association between breast cancer incidence and PA was analysed using multivariable logistic regression.Results379 histologically confirmed breast cancer cases and 403 controls took part. Compared to women in the lowest categories, women in the upper middle category of total PA(adjusted OR-AOR 0.44, 95% CI: 0.27, 0.78),uppermost categories of total non-vigorous PA (AOR 0.26, 95%CI:0.09,0.75), household PA(AOR 0.0.38, 95% CI: 0.20, 0.71) and occupational PA (AOR 0.64, 95% 0.40, 1.02) had a reduced risk of breast cancer following adjustment for relevant confounders. Transport and leisure PA were not significantly associated with a reduced risk of breast cancer.ConclusionThe total effect of various PA related to regular activities of Nigerian women was associated with a reduced risk of breast cancer. PA especially at household and occupational environments should be promoted as part of breast cancer prevention strategy in Nigeria.     

Bedtime misalignment and progression of breast cancer

Disruption of circadian rhythms, which frequently occurs during night shift work, may be associated with cancer progression. The effect of chronotype (preference for behaviors such as sleep, work, or exercise to occur at particular times of day, with an associated difference in circadian physiology) and alignment of bedtime (preferred vs. habitual), however, have not yet been studied in the context of cancer progression in women with breast cancer. Chronotype and alignment of actual bedtime with preferred chronotype were examined using the Morningness–Eveningness Scale (MEQ) and sleep-wake log among 85 women with metastatic breast cancer. Their association with disease-free interval (DFI) was retrospectively examined using the Cox proportional hazards model. Median DFI was 81.9 months for women with aligned bedtimes (“going to bed at preferred bedtime”) (n?=?72), and 46.9 months for women with misaligned bedtimes (“going to bed later or earlier than the preferred bedtime”) (n?=?13) (log rank p?=?0.001). In a multivariate Cox proportional hazard model, after controlling for other significant predictors of DFI, including chronotype (morning type/longer DFI; HR?=?0.539, 95% CI?=?0.320–0.906, p?=?0.021), estrogen receptor (ER) status at initial diagnosis (negative/shorter DFI; HR?=?2.169, 95% CI?=?1.124–4.187, p?=?0.028) and level of natural-killer cell count (lower levels/shorter DFI; HR?=?1.641, 95% CI?=?1.000–2.695, p?=?0.050), misaligned bedtimes was associated with shorter DFI, compared to aligned bedtimes (HR?=?3.180, 95% CI?=?1.327–7.616, p?=?0.018). Our data indicate that a misalignment of bedtime on a daily basis, an indication of circadian disruption, is associated with more rapid breast cancer progression as measured by DFI. Considering the limitations of small sample size and study design, a prospective study with a larger sample is necessary to explore their causal relationship and underlying mechanisms.     

Rest-activity circadian rhythm in breast cancer survivors at 5 years after the primary diagnosis

ABSTRACT

Rest-activity circadian rhythm (RAR) is a marker of the circadian timing system. Particular attention has been given to RAR characteristics in cancer diseases. Specifically, alterations of RAR parameters have been found, at different stages of clinical pathway, in breast cancer (BC) patients. No studies to date have analyzed RAR alterations in breast cancer survivors several years after the diagnosis. The aim of this study was to determine RAR by actigraphy in a population of BC survivors at 5 years after the primary diagnosis, and to compare their RAR characteristics with healthy controls. The study sample was 28 women: 15 BC survivors at 5 years from the primary diagnosis (BC-group) and 13 healthy controls (Ctrl-group), matched for age and body mass index. All participants have been monitored for 7 days by actigraphy to evaluate RAR. A statistically significant circadian rhythm (T = 24) was found in all 28 subjects (p < .001). The group analysis revealed a significant RAR both in BC- and Ctrl-group (p < .001). The acrophase was not different between the BC- and Ctrl-group (15:09 vs. 15:01 hr:min in BC- and Ctrl-group, respectively). In contrast, the MESOR (Midline Estimating Statistic of Rhythm) and the amplitude were lower in the BC-group with respect to the Ctrl-group. Indeed, the MESOR was 192.0 vs. 276.4 activity counts in BC- and Ctrl-group, respectively (p < .001), while the amplitude was 167.0 vs. 222.6 activity counts in BC- and Ctrl-group, respectively (p < .001). These results provide the first experimental evidence of alterations in RAR parameters in BC survivors at 5 years after the primary diagnosis. Larger studies with a prospective design are needed to assess the role of RAR in the quality of life and prognosis in BC survivors.     

Association Study of a Variable-Number Tandem Repeat Polymorphism in the Clock Gene PERIOD3 and Chronotype in Norwegian University Students

Circadian rhythms are endogenously generated cycles involving physiological parameters, such as core body temperature, hormone levels, blood pressure, sleep, and metabolism, with a period length of around 24?h. The circadian clock in mammals is regulated by a set of clock genes that are functionally linked together, and polymorphisms in clock genes could be associated with differences in circadian rhythms. A variable-number tandem repeat (VNTR) in the human clock gene PERIOD3 (PER3) has been suggested to correlate with a morning (lark) versus evening (owl) chronotype as well as with the circadian rhythm sleep disorder “delayed sleep phase disorder” (DSPD). The authors examined 432 healthy Norwegian university students in search of further support for an association between the PER3 polymorphism and diurnal preference. The Horne-Östberg Morningness-Eveningness Questionnaire (MEQ) and Preferences Scale (PS) were used to evaluate subjective chronotype. DNA samples were genotyped with respect to the 4-repeat and 5-repeat alleles of the VNTR PER3 polymorphism, and the genotype distribution was 192 (4-4), 191 (4-5), and 49 (5-5). The authors estimated that the power to detect an association of the 4-allele with preference for morningness or eveningness was 75%. The authors found no association between the PER3 clock gene and chronotype, indicating that the proposed role of PER3 needs further clarification. (Author correspondence: teresa.osland@med.uib.no)     

The Health Risk Assessment Performed in California for the Herbicide Simazine: A Case Study

Simazine, a member of the triazine group, is registered in California for weed control in soils where a wide range of crops will be (or are) planted. The health risks from simazine use in California were recently assessed by the California Department of Pesticide Regulation (CDPR) for all potential (acute and long-term) exposure scenarios relevant to Californian residents and workers. The results of the CDPR risk assessment indicate that current exposure levels in many of the scenarios under consideration are not health protective for the people in California. The main objective of the present summary report (i.e., case study) was two-fold, both for offering a forum to advance further scientific discussion: (1) to highlight the toxicity and exposure data as well as the assumptions used in the CDPR simazine risk assessment and then (2) to systematically requalify the uncertainties and complexities involved in terms of the toxicity and exposure appraisals given in that risk assessment. In both attempts, the focus was more on residential exposures for young children and women of child-bearing age in that simazine was reportedly seen to exhibit neuroendocrine effects across a variety of species.     

E-cadherin deregulation in breast cancer

E-cadherin protein (CDH1 gene) integrity is fundamental to the process of epithelial polarization and differentiation. Deregulation of the E-cadherin function plays a crucial role in breast cancer metastases, with worse prognosis and shorter overall survival. In this narrative review, we describe the inactivating mechanisms underlying CDH1 gene activity and its possible translation to clinical practice as a prognostic biomarker and as a potential targeted therapy.     

Plasma protein carbonyl levels and breast cancer risk

To study the role of oxidative stress in breast cancer risk, we analysed plasma levels of protein carbonyls in 1050 cases and 1107 controls. We found a statistically significant trend in breast cancer risk in relation to increasing quartiles of plasma protein carbonyl levels (OR = 1.2, 95% CI = 0.9-1.5; OR = 1.5, 95% CI = 1.2-2.0; OR = 1.6, 95% CI = 1.2-2.1, for the 2(nd), 3(rd) and 4(th) quartile relative to the lowest quartile, respectively, P for trend = 0.0001). The increase in risk was similar for younger (<50 years) and older women, more pronounced among women with higher physical activity levels (0.7 hrs/week for 4(th) quartile versus lowest quartile OR = 2.0, 95% CI = 1.4-3.0), higher alcohol consumption (> or = 15 grams/day for 4(th) quartile versus lowest quartile OR = 2.3, 95% CI = 1.1-4.7), and hormone replacement therapy use (HRT, OR = 2.6, 95% CI = 1.6-4.4 for 4(th) quartile versus lowest quartile). The multiplicative interaction terms were statistically significant only for physical activity and HRT. The positive association between plasma protein carbonyl levels and breast cancer risk was also observed when the analysis was restricted to women who had not received chemotherapy or radiation therapy prior to blood collection. Among controls, oxidized protein levels significantly increased with cigarette smoking and higher fruit and vegetable consumption, and decreased with alcohol consumption >30 grams per day. Women with higher levels of plasma protein carbonyl and urinary 15F(2t)-isoprostane had an 80% increase in breast cancer risk (OR = 1.8, 95% CI = 1.2-2.6) compared to women with levels below the median for both markers of oxidative stress. In summary, our results suggest that increased plasma protein carbonyl levels may be associated with breast cancer risk.     

A novel autophagy-related lncRNA prognostic risk model for breast cancer

Long non-coding RNAs (lncRNAs) are well known as crucial regulators to breast cancer development and are implicated in controlling autophagy. LncRNAs are also emerging as valuable prognostic factors for breast cancer patients. It is critical to identify autophagy-related lncRNAs with prognostic value in breast cancer. In this study, we identified autophagy-related lncRNAs in breast cancer by constructing a co-expression network of autophagy-related mRNAs-lncRNAs from The Cancer Genome Atlas (TCGA). We evaluated the prognostic value of these autophagy-related lncRNAs by univariate and multivariate Cox proportional hazards analyses and eventually obtained a prognostic risk model consisting of 11 autophagy-related lncRNAs (U62317.4, LINC01016, LINC02166, C6orf99, LINC00992, BAIAP2-DT, AC245297.3, AC090912.1, Z68871.1, LINC00578 and LINC01871). The risk model was further validated as a novel independent prognostic factor for breast cancer patients based on the calculated risk score by Kaplan-Meier analysis, univariate and multivariate Cox regression analyses and time-dependent receiver operating characteristic (ROC) curve analysis. Moreover, based on the risk model, the low-risk and high-risk groups displayed different autophagy and oncogenic statues by principal component analysis (PCA) and Gene Set Enrichment Analysis (GSEA) functional annotation. Taken together, these findings suggested that the risk model of the 11 autophagy-related lncRNAs has significant prognostic value for breast cancer and might be autophagy-related therapeutic targets in clinical practice.