Cancer and obesity

The prevalence of obesity is increasing worldwide. Obesity is also a major risk factor for developing chronic diseases, including malignancies thereby increasing the risk of several types of tumors such as breast, endometrium, colon, prostate and kidney cancer. The mechanisms associated with obesity and insulin resistance, hormonal regulation and other proinflammatory factors are also involved in neoplastic processes including: cell proliferation, carcinogenesis, and angiogenesis vascularization. In addition to contributing to cancer pathogenesis obesity is associated with comorbidities and poor prognosis in cancer patients. The aim of this review is to describe some of the mechanisms involved in the association of obesity and malignancies.     

Utility of alpha-methylacyl coenzyme A racemase (p504s antibody) as a diagnostic immunohistochemical marker for cancer.

Alpha-methylacyl-coenzyme A racemase (AMACR; P504S) is a mitochondrial and peroxisomal enzyme involved in the metabolism of branched-chain fatty acid and bile acid intermediates. Recently, AMACR has been demonstrated to be overexpressed in localized and metastatic prostate cancer and in high-grade prostatic intraepithelial neoplasia but not in normal prostatic glands, suggesting that it may be an important tumor marker. This study examines AMACR expression in a variety of human cancers to assess its viability as a tumor marker in the clinical setting. Two hundred sixty-three cancers from different sites were examined in three multitumor tissue micro arrays, which included two or three tissue cores (1.0 mm in diameter) from each neoplastic and normal tissue specimen. Cancers studied included breast (94 cases), prostate (38), lung (28), endometrium (27), colon (29), ovary (26), and melanoma (21). Normal tissues in the microarray were prostate (15), lung (6), endometrium (5), colon (4), ovary (2), and skin (3). Sections were immunostained, after prior pressure cooker antigen retrieval, using rabbit monoclonal AMACR antibody (1:40) (Zeta Corp, Sierra Madre, CA) and horseradish peroxidase-labeled polymer conjugated secondary antibody (Envision, Dako, Carpinteria, CA). A section of prostate cancer and prostatic intraepithelial neoplasia was used as positive control. Protein expression was scored as negative, weak (faint cytoplasmic or granular apical staining), moderate (diffuse granular cytoplasmic stain), and strong (diffuse intense cytoplasmic stain). Only moderate and strong staining was considered as positive staining, based on prior work. AMACR protein overexpression was found in several cancers, including prostate (34/38 [89.5%]), colon (13/29 [44.8%]), lung (4/28 [14.3%]), melanoma (2/21 [9.5%]), endometrium (2/27 [7.4%]), and breast (3/94 [3.2%]). None of the ovarian cancers (26 cases) demonstrated AMACR overexpression. AMACR expression was not present in any of the normal tissues nor in benign prostatic tissue associated with prostate carcinomas. This study suggests that AMACR is potentially an important tumor marker, particularly for prostate and colon cancer. It may be a useful adjunct to an immunohistochemical panel employed in the differential diagnosis of colon versus ovarian and breast carcinoma; the latter two infrequently express AMACR.     

Neoplastic diseases in families of breast cancer patients.

OBJECTIVE--To investigate whether the risk of cancer at all sites, and at individual sites other than breast, prostate, ovaries, and endometrium, is increased among relatives of breast cancer patients compared with the general population. DESIGN--A cohort of family members of breast cancer patients was established. The probands were chosen by year of birth or time of diagnosis. Any influence of knowledge of the cancer experience of the relatives has been avoided. The risk estimates are based on expected numbers computed from age and time specific incidence rates for the Icelandic population. SETTING--Iceland. SUBJECTS--The population of Iceland. MAIN OUTCOME MEASURES--Relative risks by degree of relatedness and age of proband. RESULTS--The relative risk of cancer at all sites is raised for males and females. This is more than expected based on the known familial risk of breast cancer, prostate, and ovarian cancer. The excess risk of breast, prostate, and ovarian cancer is confirmed, but not that of cancer of the endometrium. The risk of cancer of the pancreas in both sexes and the stomach and kidneys in females is significantly raised. No evidence was found for decreased risk for any cancer type. CONCLUSIONS--The risk of cancer at all sites in relatives of breast cancer patients is increased. In addition to the risk of breast, prostate, and ovarian cancer, the risk of pancreas cancer and cancer of the stomach and kidneys in females is raised, but the last mentioned observations need further confirmation.     

Breast cancer and cigarette smoking

It has been suggested that cigarette smoking may reduce the incidence of breast cancer, perhaps by as much as 20 per cent. To evaluate the relation between breast-cancer risk and smoking, we studied 2160 women with breast cancer and 717 controls who had been admitted to the hospital for cancer of the ovary, cancer of the colon or rectum, malignant melanoma, or lymphoreticular cancers. As compared with women who had never smoked, the estimated relative risk of breast cancer was 1.1 for current smokers of any amount (95 per cent confidence interval, 0.9 to 1.3), and 1.0 (0.8 to 1.3) for heavy smokers (15 or more cigarettes per day). Allowance for all identified potential confounding factors did not materially alter the results. There was no indication that age at commencement of smoking was related to the risk, nor was there evidence of an effect of smoking within the categories of age at first pregnancy or age at menopause. The data provide evidence against the hypothesis that smoking may reduce the incidence of breast cancer by 20 per cent.     

Insulin resistance, obesity and breast cancer risk

Breast cancer (BC) is one of the most important problems of public health. Among the avoidable risk factors during a woman's life, overweight and obesity are very important ones. Furthermore they are increasing worldwide. The risk of breast cancer is traditionally linked to obesity in postmenopausal women; conversely, it is neutral or even protective in premenopausal women. Since the initiator and promoter factors for BC act over a long time, it seems unlikely that the menopausal transition may have too big an impact on the role of obesity in the magnitude of the risk. We reviewed the literature in an attempt to understand this paradox, with particular attention to the body fat distribution and its impact on insulin resistance. The association of insulin resistance and obesity with BC risk are biologically plausible and consistent. Estradiol (E2) and IGFs act as mitogens in breast cancer cells. They act together and reciprocally. However the clinical and biological methods to assess the impact of insulin resistance are not always accurate. Furthermore insulin resistance is far from being a constant feature in obesity, particularly in premenopausal women; this complicates the analysis and explains the discrepancies in large prospective trials. The most consistent clinical feature to assess risk across epidemiological studies seems to be weight gain during lifetime. Loss of weight is associated with a lower risk for postmenopausal BC compared with weight maintenance. This observation should be an encouragement for women since loss of weight may be an effective strategy for breast cancer risk reduction.     

Heme of consumed red meat can act as a catalyst of oxidative damage and could initiate colon, breast and prostate cancers, heart disease and other diseases

Dietary epidemiological studies indicate correlations between the consumption of red meat and/or processed meat and cancer of the colon, rectum, stomach, pancreas, bladder, endometrium and ovaries, prostate, breast and lung, heart disease, rheumatoid arthritis, type 2 diabetes and Alzheimer's disease. The correlation of all these major diseases with dietary red meat indicates the presence of factors in red meat that damage biological components. This hypothesis will focus on the biochemistry of heme compounds and their oxidative processes. Raw red meat contains high levels of oxymyoglobin and deoxymyoglobin and oxyhemoglobin and deoxyhemoglobin and cytochromes in muscle and other tissues. Cooked and processed meat contain hemichromes and hemochromes. After being eaten heme proteins are hydrolyzed to amino acids and peptides and the heme group which is coordinated with strong ligands. The iron of heme coordinates to the sulfur, nitrogen or oxygen of amino acids and peptides and other biological components. The coordinated heme groups are absorbed and transported by the blood to every organ and tissue. Free and coordinated heme preferentially catalyze oxidative reactions. Heme catalyzed oxidations can damage lipids, proteins, DNA and other nucleic acids and various components of biological systems. Heme catalysis with hydroperoxide intermediates can initiate further oxidations some of which would result in oxidative chain reactions. Biochemical and tissue free radical damage caused by heme catalyzed oxidations is similar to that resulting from ionizing radiation. Oxidative biochemical damage is widespread in diseases. It is apparent that decreasing the amount of dietary red meat will limit the level of oxidative catalysts in the tissues of the body. Increasing consumption of vegetables and fruits elevates the levels of antioxidative components, for example, selenium, vitamin E, vitamin C, lycopene, cysteine-glutathione and various phytochemicals. These detrimental processes of heme catalysis of oxidative damage hypothesized here are not well recognized. More investigative studies in this field need to be done.     

Associations of single nucleotide polymorphisms in the adiponectin gene with adiponectin levels and cardio-metabolic risk factors in patients with cancer

Objectives: The aims of this study are to (1) study the influence of polymorphisms in adiponectin gene on adiponectin levels and potential associations with breast, prostate and colon cancer; (2) investigate the associations of adiponectin levels with other adipokines and breast, prostate and colon cancers. Subjects: We measured fasting adiponectin, leptin, insulin, Sex steroids in 132 (66 females, 66 males) cancer patients and 68 age and sex matched apparently healthy subjects. Body Mass Index (BMI) and waist circumference were used as indices of obesity. Insulin Resistance was assessed using Homeostasis Model Assessment (HOMA). Three single nucleotide polymorphisms (SNP rs182052 (G-10066-A), SNP rs1501299 (276G > T), SNP rs224176 (45T > G) in adiponectin gene were studied using Real Time Polymerase Chain Reaction. Results: GG genotype of SNP rs1501299 was significantly associated with higher levels of adiponectin (OR=1.2, 95%CI(1.03–1.3), p = 0.02); breast (OR=8.6, 95%CI(1.03–71), p = 0.04), colon cancers (OR= 12, 95%CI(1.2–115), p = 0.03). GT genotype was also associated significantly with colon cancer (OR=2.6, 95%CI (1.1–6), p = 0.03). However SNP rs224176 was associated with only breast cancer. Conclusion: Our results demonstrate that adiponectin gene SNP rs1501299 and SNP rs224176 may be the predisposing factors in some cancers but our results differ from what has been reported in other populations suggesting a complex relationship between genetic variations and phenotypic adiponectin levels.     

Chemokines, chemokine receptors, and cancer metastasis

It is clear from large clinical studies that selected chemokine receptors are often up-regulated in a large number of common human cancers, including those of the breast, lung, prostate, colon, and melanoma. Chemokine receptors and their corresponding chemokine ligands have been demonstrated to play a number of nonredundant roles in cancer metastasis to vital organs as well as regional lymph nodes, the most frequent site of cancer metastasis. Chemokine receptors may potentially facilitate tumor dissemination at several key steps of metastasis, including adherence of tumor cells to endothelium, extravasation from blood vessels, metastatic colonization, angiogenesis, proliferation, and protection from the host response via activation of key survival pathways such as phosphatidylinositol-3 kinase and Akt. It is interesting that many of these roles are reminiscent of their functions in leukocyte and stem cell trafficking. Lastly, we discuss therapeutic applications for chemokine receptor antagonists in cancer therapy.     

Parathyroid hormone may be a cancer promoter - an explanation for the decrease in cancer risk associated with ultraviolet light, calcium, and vitamin D

Epidemiological studies reporting an inverse association between sunlight exposure and risk for cancers of the breast, colon, and prostate, have not yet been explained. Since ultraviolet (UV) light promotes dermal vitamin D generation, studies suggesting that dietary calcium and vitamin D may likewise have cancer-preventive activity are potentially of relevance. UV light, calcium, and vitamin D have the common property of suppressing parathyroid hormone (PTH) production; these considerations raise the possibility that PTH may have promotional activity for certain cancers. PTH might function indirectly in this regard, by increasing hepatic production of the progression growth factor IGF-I, a likely cancer promoter. A more direct role is suggested by recent evidence that many cancers express receptors for PTH/PTH-related protein; these receptors mediate co-mitogenic and/or pro-invasive signals in some cancers. High risk for previous or concurrent neoplasms has been reported in patients with parathyroid adenomas. In light of the increase in cancer risk associated with hypertension, it is notable that PTH levels are typically increased in salt-sensitive hypertensives. Prospective case-control studies examining serum PTH in relation to subsequent cancer risk appear warranted.     

Prostate cancer is part of the hereditary non-polyposis colorectal cancer (HNPCC) tumor spectrum

The recognized urologic tumor spectrum in hereditary non-polyposis colon cancer includes ureteral and renal pelvis malignancies. Here, we report a family in which the proband, who had three metachronous adenocarcinomas of the colon and rectum (at ages 54, 57, and 60), presented with an adenocarcinoma of the prostate at age 61. Immunohistochemical (IHC) staining of colonic, rectal, and prostatic tumor tissues demonstrated lack of expression of both MSH2 and MSH6. Accordingly, microsatellite instability (MSI) was found in the rectal, colonic, and prostatic tumors. The kindred complies with the Amsterdam criteria for HNPCC, as five members over three generations had colorectal cancer. Molecular investigations were initiated when the proband's son presented with an adenocarcinoma of the colon at age 35. Southern blotting analysis of genomic DNA led to identification of a novel genomic deletion encompassing exon 5 of the MSH2 gene. Although prostate cancer has occasionally been described in HNPCC families, to the best of our knowledge, this is the first report where the MSI and IHC analysis of the prostatic adenomcarcinoma clearly link its aetiology to the germline mismatch repair mutation. Hence, prostate cancer should be included in the HNPCC tumor spectrum.     

Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank

PurposeGenome-wide association studies have identified hundreds of single nucleotide variations (formerly single nucleotide polymorphisms) associated with several cancers, but the predictive ability of polygenic risk scores (PRSs) is unclear, especially among non-Whites.MethodsPRSs were derived from genome-wide significant single-nucleotide variations for 15 cancers in 20,079 individuals in an academic biobank. We evaluated the improvement in discriminatory accuracy by including cancer-specific PRS in patients of genetically-determined African and European ancestry.ResultsAmong the individuals of European genetic ancestry, PRSs for breast, colon, melanoma, and prostate were significantly associated with their respective cancers. Among the individuals of African genetic ancestry, PRSs for breast, colon, prostate, and thyroid were significantly associated with their respective cancers. The area under the curve of the model consisting of age, sex, and principal components was 0.621 to 0.710, and it increased by 1% to 4% with the inclusion of PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, area under the curve was overall higher in the model without the PRS (0.723-0.810) but increased by <1% with the inclusion of PRS for most cancers.ConclusionPRS moderately increased the ability to discriminate the cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.     

Microsatellite instability analysis in hereditary non-polyposis colon cancer using the Bethesda consensus panel of microsatellite markers in the absence of proband normal tissue

Background  

Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant syndrome predisposing to the early development of various cancers including those of colon, rectum, endometrium, ovarium, small bowel, stomach and urinary tract. HNPCC is caused by germline mutations in the DNA mismatch repair genes, mostly hMSH2 or hMLH1.     

Complex genetic predisposition to cancer in an extended HNPCC family with an ancestral hMLH1 mutation.

Hereditary non-polyposis colorectal cancer (HNPCC) is characterised by a genetic predisposition to develop colorectal cancer at an early age and, to a lesser degree, cancer of the endometrium, ovaries, urinary tract, and organs of the gastrointestinal tract other than the colon. In the majority of families the disease is linked to mutations in one of the two mismatch repair genes, hMSH2 or hMLH1. We have found a novel hMLH1 nonsense mutation in a Swiss family with Lynch syndrome, which has been transmitted through at least nine generations. A different tumour spectrum of neoplasms of the skin, soft palate, breast, duodenum, and pancreas was observed in three branches of this family, where there was a virtual absence of colonic tumours. The hMLH1 mutation could not be detected in members of these branches suggesting that at least a second genetic defect predisposing to cancer is segregating in part of the kindred.     

Overexpression of the fat mass and obesity associated gene (FTO) in breast cancer and its clinical implications

Background and purpose: Incidence of breast cancer is increasing and seems to be associated with fatty foods, metabolism, and so on. The fat mass and obesity associated gene (FTO) has been intensively investigated in diabetes, obesity and the other diseases. Previous studies have reported that FTO SNPs are associated with breast cancer risk. Here, we investigated the expression of FTO in human breast cancer tissues and its relationship with the clinicopathological features. Methods: In this retrospective study, tissues from 79 patients with breast cancer were collected, as well as 43 cases of adjacent breast tissues. Immunohistochemistry was used to detect the expression of FTO. Statistical analysis was performed to assess the association between FTO expression and the clinicopathological features of breast cancer. Results: FTO was expressed in both mammary epithelial and breast cancer tissues, but with different degree. The expression level of FTO in breast cancer tissues was significantly higher than that in the adjacent breast tissues (P < 0.001). The percentage of FTO-positive expression in cases with hormone receptor (HR) negative and HER2 amplification was significantly higher than that in those with HR positive and HER2 negative (P = 0.001, P < 0.001). The positivity rate of FTO in breast cancer with P53 positive and histological grade 3 seemed to be higher than that with P53 negative and histological grade 1 or 2, respectively (P = 0.077, P = 0.082). There was no association between FTO expression and age, T stage, LN status, TNM stage, Ki67, and BMI in breast cancer. Besides, FTO expression in HER2-overexpressed subtype was significantly higher than that in Triple-negative and Luminal A/B1 subtypes (P < 0.001). Conclusion: Our study suggests that FTO expression may have a vital role in the carcinogenesis of breast cancer, especially in HER2-overexpressed breast cancer.     

A cylindrical model of the rectum: comparing dose-volume,dose-surface and dose-wall histograms in the radiotherapy of prostate cancer

The calculation of the percentage cumulative histogram of the rectal wall (DWH) in prostate cancer radiotherapy may be subject to large uncertainties due to the difficulty of assessing the wall thickness on CT images. For this reason often only the external contour is used to define the rectum and then the percentage cumulative dose-volume histogram (DVH) of the rectum including any filling is calculated as a 'surrogate' for the DWH. More recently, other approaches using only the external contour have been proposed to estimate the DWH such as the percentage normalized dose-surface histograms (NDSH). A similar concept can be used when considering the solid rectum (the percentage normalized DVH, NDVH). The purpose of this investigation was to assess the relationships between rectal DVH, NDVH, DSH, NDSH and DWH in the common case of three- and four-field techniques in prostate cancer irradiation. Analytical relationships between the above parameters have been derived for a cylindrical rectum model in the case of three- and four-field techniques. The model is applied to the case of an empty rectum, a full rectum and to the more realistic mixed full/empty rectum situation for a four-field technique delivering 76 Gy (ICRU dose) with 18 MV x-rays. Different positions of the lateral beam with respect to the rectum axis were simulated. In the case of no lumen variation along the z-axis, the DWH is found to be very close to the DVH and to the DSH for empty and full rectum, respectively. The largest differences (up to 15%) between DVH and DSH were seen in the high-dose region (>70 Gy). In the more realistic case of lumen variation along the z-axis, the DWH always lies between NDVH and NDSH and, excluding the full-rectum situation, the DWH differs from the DVH by less than 7% in the 50-75 Gy range. In the case of significant portions of rectum being completely shielded, the DVH may differ from the NDVH/NDSH/DWH by up to 10-15%. In most clinical situations NDVH is within a few per cent of DWH, whilst NDSH may differ from DWH by up to 15-20%, especially in the high-dose region (V70). In conclusion, for most situations, the DVH is highly correlated with NDVH and DWH. A high degree of consistency between NDVH and DWH was found in most clinical cases whilst largest deviations between NDSH and DWH were evident in the high-dose region (70-75 Gy). In the less common case of a very full rectum a poorer correlation between DVH/NDVH and DWH was found whilst NDSH mimicked the DWH very well. In summary, except for the case of a 'very full' rectum, NDVH may be used as a robust surrogate for DWH. The DVH seems to be sufficiently robust if the rectum is prevalently empty.     

Nutrition and breast cancer

Breast cancer incidence is rising worldwide with an increase in aggressive neoplasias in young women. Suspected factors responsible for the global increase include lifestyle changes, notably diet. Currently accepted risk factors directly linked to diet are greater body weight and alcohol consumption. Weight gain in adulthood is associated with increased risk of breast cancer in post-menopausal women, suggesting that weight gain before and around menopausal age may be determinant for breast cancer development among postmenopausal women. Numerous studies also show an impact of specific diets and nutrients – fatty acids, carbohydrates, vitamins B, D, carotenoids, phytoestrogens, fiber – on breast cancer risk, and evidence supports a mechanistic basis for an influence of specific nutrients. However, these studies are plagued with conflicting results. In this review, a new examination of the relationship between nutrition and breast cancer is proposed in light of recent epidemiological studies. Successful development of breast cancer prevention strategies will require identification of biological markers of dietary exposure, and to coordinate worldwide research to discern the effects of diet.     

Interaction between menopausal status and obesity in affecting breast cancer risk

Obesity has a complex relationship to breast cancer risk that differs in premenopausal and postmenopausal women. Before the menopause, the level of adiposity is inversely related to risk, indicative of a protective effect, whereas in postmenopausal women, particularly the elderly, the association is a positive one, consistent with obesity being a risk factor. The importance of high estrogen production in adipose tissue, with consequent elevation of circulating biologically available estradiol, in the promotional effect of obesity on postmenopausal breast carcinogenesis is well established; the resulting tumors express both estrogen and progesterone receptors. The mechanism(s) for the protective effect in premenopausal women is less well understood, but the breast cancers that do develop in the presence of obesity are most often estrogen and progesterone receptor negative, consistent with the selection of non-estrogen-dependent tumor cells which are dependent on growth factors such as insulin, insulin-like growth factor-I and some adipokines. The influence of menopausal status on the relationships between adiposity and breast cancer appears to be modified within each category by age; the protective effect before the menopause may be limited to younger women (<35 years), and the adverse effect was found to apply specifically to older postmenopausal women. Although randomized trials of weight reduction for postmenopausal breast cancer prevention have not been performed, observational studies suggested that risk reduction does occur; in addition, other health benefits of weight control need to be considered regardless of menopausal status.     

Covariance of breast cancer incidence with smoking-, oestrogen- and diet-related cancers in pre- and postmenopausal women in Sweden

Effects of smoking on breast cancer risk remains controversial. Tar products have been claimed to increase risk, antioestrogenic effects to reduce risk. Another possibility is that associations to smoking have been confounded by diet. The increasing incidence of breast cancer from 1960 to 1994 in Sweden is parallel to that of lung cancer and the increasing proportion of female smokers. The incidence of endometrial and colon cancer was in premenopausal women negatively and in postmenopausal women positively related to the incidence of breast cancer. Possible explanations and hypotheses to the different co-variance between breast cancer and lung, endometrial and colon cancer in pre- and postmenopausal women are discussed from the perspectives of smoking, sex hormones and diet. It is concluded that the strong and specific positive relationship between breast and lung cancer in premenopausal women is compatible with the hypothesis that aromatic hydrocarbons may be involved in the causation of disease.     

Epidemiology and prevention of cancer]

Primary prevention is of priority in cancer control. This primarily applies to malignant neoplasms whose direct cause is smoking. Modifications in nutrition by consuming more fresh vegetables and fruits, by reducing calories, by enhancing physical activity, and correspondingly, a decrease in body weight will result in lower incidence of cancer of the stomach, colon, breast, uterine body, prostate and affect the risk for malignancy associated with smoking and other environmental carcinogenic factors. Prevention of infectious exposures, including vaccination, is the most effective method for controlling cancer of the cervix uteri and liver, some leukemias and lymphomas, H. pylori-associated gastric cancer. The most important components of cancer control are to monitor the enterprises, ambient and room air for carcinogens and to lower adverse impact of ultraviolet and ionizing radiation on man. Progress in molecular biology enables one to involve into carcinogenesis at its each stage. The risk associated with carcinogenic exposure can be assessed by taking into account not only the carcinogenicity of an environmental factor and its dosage, but also individual sensitivity. Information on specific molecular genetic changes that are specific for different carcinogenic substances and tumors, the so-called finger prints, may be used for identification of a carcinogenic factor and correspondingly for prevention, as well as preclinical diagnosis and gene therapy at early stages of carcinogenesis.     

Effects of estrogens and hormone replacement therapy on breast cancer risk and on efficacy of breast cancer therapies

This review summarises preclinical and clinical data on effects of endogenous and exogenous estrogens on probability of breast cancer diagnosis, and on the course and efficacy of breast cancer therapies. The data indicate that higher endogenous estrogen exposure (e.g. pregnancy, early menarche and late menopause, estrogen levels in future breast cancer patients, obesity) or exogenous estrogens (oral contraceptives; hormone replacement therapies) may be associated with an increased probability of breast cancer diagnosis. However, there is little evidence that estrogens have deleterious effects on the course of breast cancer. Moreover, increased incidence of breast cancer diagnosis after prolonged hormone replacement therapy (HRT) use seems to be associated with clinically less advanced disease. In studies assessing both diagnosis and mortality, HRT is frequently associated with reduced mortality compared to never users. The interaction of progestagens and estrogens on the probability of breast cancer diagnosis is complex and dependent on type of progestagens and regimens employed. Efficacy of current treatment modalities for breast cancer (surgery, irradiation, adjuvant therapy or chemotherapy) is not negatively influenced by estrogens at concentrations considerably higher than those attained with current HRT preparations. Although it cannot be excluded that estrogens increase the probability of breast cancer diagnosis, available data fail to demonstrate that, once breast cancer has been diagnosed, estrogens worsen prognosis, accelerate the course of the disease, reduce survival or interfere with the management of breast cancer. It may therefore be concluded that the prevalent opinion that estrogens and estrogen treatment are deleterious for breast cancer, needs to be revisited. However, results of ongoing prospective, randomised clinical trials with different HRT regimens in healthy women or breast cancer survivors are needed to provide more definite conclusions about risks and benefits of HRT.