Does genetic counseling have any impact on management of breast cancer risk?

Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.     

Is there an adverse effect of sons on maternal longevity?

Recent years have witnessed the emergence of a literature examining the effects of giving birth to sons on postmenopausal longevity in pre-industrial mothers. The original paper in this lineage used a sample (n=375) of Sami mothers from northern Finland and found that, relative to daughters, giving birth to sons substantially reduced maternal longevity. We examine this hypothesis using a similar and a much larger sample (n=930) of pre-industrial Sami women from northern Sweden, who in terms of their demographic, sociocultural and biological conditions, closely resemble the original study population. In contrast to the previously reported results for the Sami, we find no evidence of a negative effect of sons on maternal longevity. Thus, we provide the most compelling evidence to date that the leading result in the literature must be approached with scepticism.     

Is there a real risk of radiation-induced breast cancer for postmenopausal women?

The risk of radiation-induced breast cancer decreases with increasing age at exposure. Thus, for calculating the individual risk for a patient undergoing mammography, age-related risk coefficients need to be used. In this report, the results of epidemiological studies on risks of radiation-induced breast cancer are reviewed indicating that the available data do not show the risk to be enhanced for women exposed at the age of 55 years or older. This lack of evidence is reflected by the fact that the risk coefficients recommended by national and international advisory bodies differ by a factor of 10 or more for age at exposure of 50–60 years or older. A hypothesis is proposed indicating that the risk of radiation-induced breast cancer might decrease considerably at the time of menopause. The hypothesis is based on the following line of arguments: (1) evidence has accumulated from molecular genetic studies indicating that the development of colorectal cancer requires a cascade of subsequent mutations consisting of at least seven genetic events. (2) For colorectal cancer, the annual rates of incidence and mortality increase with age to the power of 5–6. Thus, the number of mutation steps (minus 1) is approximately reflected by the power of age dependence. (3) For western populations, the incidence and mortality of breast cancer up to the age of about 50 years increase with age to the power of about 6, indicating that a similar number of genetic events might be involved in development of breast cancer as has been identified for colorectal cancer. (4) For women aged 50 years or older, breast cancer occurs at an annual rate that is about proportional to age or age squared. This may mean that after menopause, the processes in the multistep mutation cascade leading to breast cancer are slowed down by a factor of about 4 or more. (5) The constant relative risk model of radiation carcinogenesis implies for solid cancers that radiation acts by inducing additional mutations in the earlier steps of the multistep cascade. It is suggested that the break-point in the age-specific annual rate of breast cancer incidence at menopause is associated with a corresponding drop in radiation sensitivity with respect to induction of breast cancer. Received: 8 January 2001 / Accepted: 20 March 2001     

Is there any effect of renal failure on the hepatic regeneration capacity following partial hepatectomy in rats?

The effects of renal dysfunction on liver regeneration capacity have not been fully elucidated before, although many patients with renal failure are subjected to hepatectomy due to hepatobiliary diseases. In this study, we sought to determine the effects of renal dysfunction on the hepatic regeneration capacity using rat chronic renal failure model. After establishing chronic renal failure (CRF group) by semi-total renal resection, the rats were subjected to 70% partial hepatectomy (PHx). Rats without renal failure were used as control (Sham group). The hepatic regeneration rate, histology of the liver, clearance of indocyanine green into the bile, and the expression of hepatic regeneration-associated genes in the liver were evaluated. The hepatic regeneration rate was lower in CRF group as compared to Sham group on day 1 after PHx. Mitotic index evaluated by histologic examination on day 1 after PHx was also significantly lower in CRF group. However, no difference in these indices was observed on day 2 and 7 between Sham and CRF. Indocyanine green clearance rate was almost identical between Sham and CRF on day 7 following PHx. The baseline expressions of the hepatic regeneration-associated genes, such as IL-6, TNF-alpha, HGF, c-fos, and c-jun, in the liver of CRF were significantly lower than those of Sham. However, the rate of upregulation of these genes was not significantly different between Sham and CRF. These results clearly demonstrate that the renal dysfunction, although initially delays the onset, does not suppress the total hepatic regeneration capacity following partial hepatectomy. The function of the regenerated liver on day 7 after PHx also was not different. Our results provide a possibility that the hepatectomy can be indicated even for the patient with a chronic renal failure.     

Tissue‐disruption‐induced cellular stochasticity and epigenetic drift: Common origins of aging and cancer?

Age‐related and cancer‐related epigenomic modifications have been associated with enhanced cell‐to‐cell gene expression variability that characterizes increased cellular stochasticity. Since gene expression variability appears to be highly reduced by—and epigenetic and phenotypic stability acquired through—direct or long‐range cellular interactions during cell differentiation, we propose a common origin for aging and cancer in the failure to control cellular stochasticity by cell–cell interactions. Tissue‐disruption‐induced cellular stochasticity associated with epigenetic drift would be at the origin of organ dysfunction because of an increase in phenotypic variation among cells, ultimately leading to cell death and organ failure through a loss of coordination in cellular functions, and eventually to cancerization. We propose mechanistic research perspectives to corroborate this hypothesis and explore its evolutionary consequences, highlighting a positive correlation between the median age of mass loss onset (a proxy for the onset of organ aging) and the median age at cancer diagnosis.     

The synthesis and anticancer effects of a range of natural and unnatural hop β-acids on breast cancer cells

The β-acids derived from hops (Humulus lupulus L.) are polyphenols classified as lupulones. As part of our on-going interest in the pharmacognosy of these natural products we were keen to investigate the anticancer activity of lupulone 1 as well as individual lupulone congeners. To achieve this we undertook the synthesis of natural as well as unnatural lupulone derivatives and evaluated them for their anticancer activity against the breast cancer cell lines MCF-7 and MDA-MB-231.The results of our investigations revealed that all of the novel unnatural lupulone derivatives that were synthesised were found to be more toxic to MDA-MB-231 cell lines at 72 h than the parent lupulone 1 itself (except for the α-substituent R¹ was CH₃). Further investigations confirmed that the novel lupulone derivatives were very efficient at killing cancer cells by apoptosis but appear to do so in a time-dependant process. This outcome may be of great significance as MDA-MB-231 cell lines are characterised by an aggressive phenotype with a propensity to invade other tissue, to form metastases as well as an ability to become insensitive to chemotherapeutic agents.     

Is there safety‐in‐numbers for prey?

The abundance of prey affects the rate of predation, but little consensus exists on whether this enhances or reduces per capita mortality. Studies of aggregating prey in marine habitats generally emphasise that the probability of predation of any individual is the reciprocal of the number of prey within a school. A field experiment tested the alternative hypotheses that predation by predatory fish on schooling prey (1) increased with an increase in the number of prey per school and that this caused (2) survival to be lower in schools with more individuals. The number of prey (juvenile Acanthochromis polyacanthus ) per school was manipulated in replicate treatments with natural densities of large predatory fish (open plots) and treatments without large predatory fish (exclusion cages). Large predatory fish preyed on juveniles in a density-dependent manner and this was the key source of density-dependent mortality in plots open to all predators. There was some suggestion that small predatory fish also prey on juveniles in a density-dependent manner, but this was weak and did not translate into density-dependent mortality of juveniles. It would appear that aggregation of prey may be a successful strategy against predation from some predators, but not always every predator, or all predators in combination.     

The effect of culture and membrane potential on Goα expression in neonatal rat cardiac myocytes

The effects of culture and membrane potential on G_o39 expression were examined in neonatal rat cardiac myocytes. During six days of culture, the amount of G_o39 in myocytes increased six-fold. The increase in G_o39 appeared to be programmed, since G_o39 of rat hearts also increased in vivo within three days after birth before declining by six days after birth. Furthermore, the age of the rat from which cardiac myocytes were isolated determined the amount of G_o39 that accumulated in cultured cells with myocytes from two day-old rats producing more G_o39 than myocytes from six day-old rats. In addition, agents which alter membrane potential (KCl and bupivacaine) inhibited the accumulation of G_o39 in cultured myocytes. In an attempt to identify the signaling pathway in which cardiac G_o39 is involved, muscarinic receptor-stimulated inositol phosphate production was examined, but was found to be comparable in myocytes that had six-fold differences in G_o39 content. Thus G_o39 does not appear to couple muscarinic receptors to phospholipase C in rat cardiac myocytes.     

Viruses and oral cancer. Is there a link?

Oral squamous cell carcinoma (OSCC) is the most common malignant tumour of the oral cavity. The aetiology of epithelial cancer of the head and neck is considered to be a multifactorial, sequential process. DNA viruses are found in many different cancers and are also capable of transforming cells to a malignant phenotype. Human Papilloma Virus (HPV) has been proposed as risk factors in OSCC development and HPV type 16 is the most important subtype. Other oncogenic virus species i.e., Epstein–Barr Virus and Herpes Simplex Virus Type 1 have been proposed to be involved in oral carcinogenesis. However, no convincing evidence exist that they are an established risk factor in OSCC. Therefore more studies are needed in order to clarify the different aspects of virus involvement. Here, we review the existing literature on viral involvement in oral cancer.     

Characterization of anticancer properties of 2,6-diisopropylphenol–docosahexaenoate and analogues in breast cancer cells

The present study describes the characterization and evaluation of novel anticancer conjugates, 2,6-diisopropylphenol–docosahexaenoate (PP–DHA), and its analogues including 2,4-diisopropylphenol–docosahexaenoate (DIPP–DHA), 2-isopropylphenol–docosahexaenoate (IPP–DHA), 2-cyclohexanephenol-docosahexaenoate (CHP–DHA) and phenol–docosahexaenoate (P–DHA) on breast cancer cell lines. Representative breast cancer cell lines, based on estrogen α receptor (ER) and oncogene Her-2 expression, were used and include MDA-MB-231 (ER-negative, Her-2-negative), MCF-7 (ER-positive, Her-2-negative) AU565 (ER-negative, Her-2-positive) and MDA-MB-361 (ER-positive, Her-2-positive). The PP–DHA conjugate significantly inhibited cell growth and induced cell loss in the breast cancer cell lines similarly; however, this conjugate was not effective against normal mammary epithelial cells. The effect of various conjugates were in PP–DHA > IPP–DHA > DIPP–DHA > CHP–DHA >> P–DHA order. PP–DHA and IPP–DHA conjugates were stable in human and mouse serum. Furthermore, the non-hydrolyzable amide-linked conjugate analogues affected breast cancer cells in a manner similar to that of the ester-linked conjugates. This suggests that ester-linked PP–DHA and IPP–DHA conjugates were stable during treatment to breast cancer cells due to structural hindrance. PP–DHA did not affect PPARα or PPARγ activities but its anticancer effects appear to be mediated in part though the inhibition of histone deacetylase (HDAC) activity. Further experiments are needed to confirm their molecular target and to test the effectiveness of these compounds in an in vivo model for their anticancer properties. In conclusion, these results suggest that the novel PP–DHA and IPP–DHA conjugates and their amide derivatives may be useful for the treatment of breast cancer.     

Obesity and triple‐negative‐breast‐cancer: Is apelin a new key target?

Epidemiological studies have shown that obese subjects have an increased risk of developing triple‐negative breast cancer (TNBC) and an overall reduced survival. However, the relation between obesity and TNBC remains difficult to understand. We hypothesize that apelin, an adipokine whose levels are increased in obesity, could be a major factor contributing to both tumour growth and metastatization in TNBC obese patients. We observed that development of obesity under high‐fat diet in TNBC tumour‐bearing mice significantly increased tumour growth. By showing no effect of high‐fat diet in obesity‐resistant mice, we demonstrated the necessity to develop obesity‐related disorders to increase tumour growth. Apelin mRNA expression was also increased in the subcutaneous adipose tissue and tumours of obese mice. We further highlighted that the reproduction of obesity‐related levels of apelin in lean mice led to an increased TNBC growth and brain metastases formation. Finally, injections of the apelinergic antagonist F13A to obese mice significantly reduced TNBC growth, suggesting that apelinergic system interference could be an interesting therapeutic strategy in the context of obesity and TNBC.     

Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? A Mendelian randomization study

Morning-preference chronotype has been found to be protective against breast and prostate cancer. Sex hormones have been implicated in relation to chronotype and the development of both cancers. This study aimed to assess whether sex hormones confound or mediate the effect of chronotype on breast and prostate cancer using a Mendelian Randomization (MR) framework. Genetic variants associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin, and oestradiol) (p<5×10⁻⁸) were obtained from published genome-wide association studies (n≤244,207 females and n≤205,527 males). These variants were used to investigate causal relationships with breast (nCases/nControls = 133,384/113,789) and prostate (nCases/nControls = 79,148/61,106) cancer using univariable, bidirectional and multivariable MR. In females, we found evidence for: I) Reduced risk of breast cancer per category increase in morning-preference (OR = 0.93, 95% CI:0. 88, 1.00); II) Increased risk of breast cancer per SD increase in bioavailable testosterone (OR = 1.10, 95% CI: 1.01, 1.19) and total testosterone (OR = 1.15, 95% CI:1.07, 1.23); III) Bidirectional effects between morning-preference and both bioavailable and total testosterone (e.g. mean SD difference in bioavailable testosterone = -0.08, 95% CI:-0.12, -0.05 per category increase in morning-preference vs difference in morning-preference category = -0.04, 95% CI: -0.08, 0.00 per SD increase in bioavailable testosterone). In males, we found evidence for: I) Reduced risk of prostate cancer per category increase in morning-preference (OR = 0.90, 95% CI: 0.83, 0.97) and II) Increased risk of prostate cancer per SD increase in bioavailable testosterone (OR = 1.22, 95% CI: 1.08, 1.37). No bidirectional effects were found between morning-preference and testosterone in males. While testosterone levels were causally implicated with both chronotype and cancer, there was inconsistent evidence for testosterone as a mediator of the relationship. The protective effect of morning-preference on both breast and prostate cancer is clinically interesting, although it may be difficult to effectively modify chronotype. Further studies are needed to investigate other potentially modifiable intermediates.