The Effect of Smoking on Progression from Ductal Carcinoma In Situ to Invasive Ductal Breast Carcinoma: A Retrospective Study.

BACKGROUND/AIM: If ductal carcinoma in situ (DCIS) is diagnosed by needle biopsy, invasion is often found by removing the entire tumor and performing pathological examination. Smoking is a risk factor for carcinogenesis in breast cancer. We examined the correlation between the risk of invasion found by postoperative pathology and smoking history in patients diagnosed with DCIS by preoperative biopsy. PATIENTS AND METHODS: We examined 128 patients who were diagnosed with DCIS by preoperative biopsy. Multivariate analysis was performed on the risk factors for invasion diagnosed by postoperative pathological examination in all cases diagnosed with DCIS by preoperative biopsy. RESULTS: Multivariate analysis was performed on the risk factors for invasion diagnosed by postoperative pathological examination in all cases diagnosed with DCIS by preoperative biopsy. Number of pack-years was not an independent factor (p=0.349, OR=0.329), but current-smoker status (p=0.006, OR=not calculable) was an independent factor with VAB (p=0.018, OR=0.327). CONCLUSION: Tobacco components may have an influence on the progression from DCIS to invasive ductal carcinoma.

Cadmium Exposure and Risk of Breast Cancer by Histological and Tumor Receptor Subtype in White Caucasian Women: A Hospital-Based Case-Control Study.

As the majority of experimental studies suggest cadmium being metalloestrogen, we examined cadmium/breast cancer (BC) association by histological and tumor receptor subtype in 509 invasive BC patients and 1170 controls. Urinary cadmium was determined by atomic absorption spectrometry, and categorized using tertiles of its distribution in the controls: <0.18, 0.18-0.33, >0.33 kg × 10-9/kg × 10-3 creatinine. Relative to the lowest category of urinary cadmium adjusted odds ratio (OR) of ductal BC was 1.18 (95% confidence interval (CI): 0.89-1.58) in the intermediate and 1.53 (95% CI: 1.15-2.04) in the highest category. There was a significant association for hormone receptor-positive ductal BC: ORs per category increase were 1.34 (95% CI: 1.14-1.59) for estrogen receptor-positive (ER+), 1.33 (95% CI: 1.09-1.61) for progesterone receptor-positive (PR+) and 1.35 (95% CI: 1.11-1.65) for ER+/PR+ BC. We found a significant association between cadmium and human epidermal growth factor receptor 2-negative (HER2-) ductal BC. The strongest association with cadmium was for ER+/PR+/HER2- ductal BC. The associations between cadmium and lobular BC with hormone receptor-positive and HER2- were positive but insignificant. There was no evidence that the associations with cadmium differed for cancers with different tumor histology (p-heterogeneity > 0.05). This study provides evidence that urinary cadmium is associated with the risk of hormone receptor-positive and HER2- breast cancer independent of tumor histology.

Statin Use and Breast Cancer Risk in the Nurses' Health Study.

Preclinical studies support an anticancer effect of statin drugs, yet epidemiologic evidence remains inconsistent regarding their role in breast cancer primary prevention. Here, we report an updated analysis of the association between statin use and breast cancer incidence in the Nurses' Health Study (NHS) cohort. Postmenopausal NHS participants without a cancer history were followed from 2000 until 2012 (n = 79,518). Data on statin use were retrieved from biennial questionnaires. We fit Cox regression models to estimate associations between longitudinal statin use and breast cancer incidence. Over 823,086 person-years of follow-up, 3,055 cases of invasive breast cancer occurred. Compared with never users, both former and current statin users had similar rates of invasive breast cancer incidence [former users: HRadj, 0.96; 95% confidence interval (CI), 0.82-1.1; current users: HRadj, 1.1; 95% CI, 0.92-1.3]. Associations did not differ by estrogen receptor (ER) status or histology (ductal vs. lobular carcinoma). Statin use was not associated with risk of invasive breast cancer, irrespective of histologic subtype and ER status. Statin drugs do not appear to modify processes involved in breast cancer initiation.

Levonorgestrel-releasing intrauterine system and the risk of breast cancer: A nationwide cohort study.

BACKGROUND: Prolonged steroid hormone therapy increases the risk of breast cancer, especially the risk of lobular cancer, but the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) use is controversial. In this study we aimed to test the hypothesis that risk for lobular breast cancer is elevated among LNG-IUS users. MATERIAL AND METHODS: We identified from the national Medical Reimbursement Registry of Finland the women aged 30-49 who had used LNG-IUS for the treatment or prevention of menorrhagia in 1994-2007, and from the Finnish Cancer Registry breast cancers diagnosed before the age of 55 and by the end of 2012. RESULTS: A total of 2015 women had breast cancer diagnosed in a cohort of 93 843 LNG-IUS users during follow-up consisting of 1 032 767 women-years. The LNG-IUS users had an increased risk for both ductal breast cancer [standardized incidence ratio (SIR) 1.20, 95% confidence interval (CI) 1.14-1.25] and for lobular breast cancer (SIR 1.33, 95% CI 1.20-1.46), as compared with the general female population. The highest risk was found in LNG-IUS users who purchased the device at least twice, whose SIR for lobular cancer was 1.73 (95% CI 1.37-2.15). CONCLUSIONS: The results imply that intrauterine administration of levonorgestrel is not only related to an excess risk of lobular breast cancer but also, in contrary to previous assumptions, to an excess risk of ductal breast cancer.

Carcinoma de mama en trabajadora expuesta a radiaciones ionizantes / Female Worker with breast cacinoma exposed to ionizing radiation

M.A., de 40 años de edad, es técnico especialista de radiodiagnóstico del hospital. Es una trabajadora profesionalmente expuesta a radiaciones ionizantes categoría A. Es diagnosticada de carcinoma ductal infiltrante de mama derecha. Tratamiento: tumorectomía, quimioterapia (Taxotere), Radioterapia con acelerador lineal (50 Grays) y braquiterapia con Iridio-192 (8 Grays). A los 18 meses es alta médica y acude a la consulta de Medicina del Trabajo para examen de salud tras ausencia por larga enfermedad. Consultado el Cuadro de Enfermedades Profesionales (Real Decreto 1299/2006) y el Protocolo de vigilancia sanitaria específica para radiaciones ionizantes del Ministerio de Sanidad, no aportan información útil para definir los criterios de aptitud. Se revisa historia clínica de la paciente y bibliografía y se concluye: la trabajadora es calificada APTA para el puesto de trabajo de técnico especialista de radiodiagnóstico (AU)

M.A., female, 40 years old, technical specialist hospital radiology, diagnosed with invasive ductal carcinoma of the right breast. She is a worker professionally exposed to ionizing radiation A. Medical treatment: Lumpectomy, chemotherapy (Taxotere), radiotherapy linear accelerator (50 Grays) and brachytherapy with Iridium-192 (8 Grays). After 18 months treatment, she is medically discharged and attended to the Occupational Health consultation for a health checking, after a long absence due to her illness. The Retrieved Table of Occupational Diseases (Royal Decree 1299/2006) and Specific Health Surveillance Protocol for Ionizing Radiation (Health Ministry) consulted, any useful information has been provided to define aptness criteria. Once the bibliography and the patient’s clinical history reviewed, our conclusion was that the worker was SUITABLY qualified to carry out with her x-ray technical job (AU)

Melatonin potentiates the anti-tumour effect of pravastatin in rat mammary gland carcinoma model.

Previous studies in the field of cancer research have suggested a possible role for statins in the reduction of risk in certain malignancies. The purpose of these studies was to examine the chemopreventive effects of pravastatin alone and in combination with pineal hormone melatonin in the N-methyl-N-nitrosourea-induced mammary carcinogenesis model. Pravastatin was given orally (1 00 mg/kg) and melatonin was added to the water (20 µg/ml). Chemoprevention began seven days prior to carcinogen administration and subsequently continued for 15 weeks until autopsy. At autopsy, mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. Parameters of experimental carcinogenesis, mechanism of action (biomarkers of apoptosis, angiogenesis and proliferation) and side effects after long-term treatment in animals were assessed. Pravastatin alone suppressed tumour frequency by 20.5% and average tumour volume by 15% compared with controls. Combined administration of the drugs decreased tumour frequency by 69% and lengthened tumour latency by nine days compared with control animals. The ration between high and low grade carcinomas was apparently reduced in both treated groups. The analysis of carcinoma cells showed significant expression increase in caspase-3 and caspase-7 after pravastatin treatment; however, combined treatment even more pronounced increase in the expression of both caspases. Regarding VEGFR-2 expression, a small effect in carcinomas of both treated groups was found. In plasma metabolism evaluation, pravastatin alone significantly decreased levels of glucose and triacylglycerols. Our results suggest a mild anti-neoplastic effect of pravastatin in this rat mammary gland carcinoma model. Statins co-administered with other suitable drug (e.g. melatonin) should be further evaluated for tumour-preventive properties.

Use of menopausal hormone therapy and risk of ductal and lobular breast cancer among women 55-74 years of age.

The Women's Health Initiative (WHI) randomized trials found that use of combined estrogen and progestin menopausal hormone therapy (CHT) increases breast cancer risk, but use of unopposed estrogen hormone therapy (EHT) does not. However, several questions regarding the impact of hormone use on risk of different types of breast cancer and what thresholds of use confer elevations in risk remain. We conducted a population-based case-control study among women 55-74 years of age to assess the association between menopausal hormone use and risk of invasive ductal and invasive lobular breast carcinomas. Associations were evaluated using polytomous logistic regression and analyses included 880 ductal cases, 1,027 lobular cases, and 856 controls. Current EHT and CHT use were associated with 1.6-fold [95 % confidence interval (CI): 1.1-2.2] and 2.3-fold (95 % CI: 1.7-3.2) increased risks of lobular breast cancer, respectively, but neither was associated with risk of ductal cancer. Lobular cancer risk was increased after 9 years of EHT use, but after only 3 years of CHT use. Evidence across more than a dozen studies indicates that lobular carcinoma is the type of breast cancer most strongly influenced by menopausal hormones. Here, we characterize what thresholds of duration of use of both EHT and CHT that confer elevations in risk. Despite the rapid decline in hormone therapy use the WHI results were published, study of the hazards associated with these medications remains relevant given the estimated 38 million hormone therapy prescriptions that are still filled in the United States annually.

Chemotherapeutic effect of tangeretin, a polymethoxylated flavone studied in 7, 12-dimethylbenz(a)anthracene induced mammary carcinoma in experimental rats.

Globally, breast cancer is the second most prevalent cancer among women and its incidence is amplifying alarmingly. Since genetics is believed to account for only 10% of the reported cases, the environmental factors including diet are thought to play a significant role in predisposing breast cancer. Many bioactive compounds of plant origin have been reported for their anticancer potential. Tangeretin, a pentamethoxy flavone, is a naturally occurring phytoconstituent found to be present in significant amounts in the peel of citrus fruits. Tangeretin possess a wide array of pharmacological activities such as cytostatic, anti-proliferative and antioxidant properties. In the absence of systemic studies in the literature, the present study was aimed to evaluate the chemotherapeutic potential of tangeretin in 7, 12-dimethyl benz(a)anthracene (DMBA) induced mammary carcinoma in rats. Oral treatment of tangeretin (50 mg/kg BW) to breast tumor bearing rats daily for four weeks was found to be effective against DMBA induced mammary gland carcinogenesis in female Wistar rats. The increased activities of AST, ALT, ALP, ACP, 5'-ND, γ-GT and LDH in serum of control and experimental breast cancer rats were significantly (p < 0.05) decreased to near normal levels. Further, the levels of lipid peroxide (TBARS), enzymatic antioxidants such as SOD, CAT, GPx and non-enzymatic antioxidants such as GSH, Vitamin C, Vitamin E and Phase I (cytochrome P450, cytochrome b5, EROD, MROD and PROD) and Phase II detoxification (glutathione S-transferase (GST), quinone reductase (QR)) were decreased significantly by administration of tangeretin. Immunohistochemical and western blotting studies for estrogen receptor, progesterone receptor and HER2/neu status exemplified the chemotherapeutic effect of tangeretin. Further, the histological and ultrastructural analysis of breast tissues evidenced the anti-tumorigenic nature of tangeretin. Thus, the results of the present study clearly indicate that tangeretin significantly suppresses DMBA induced breast cancer in rats.

Immunohistochemical characterization of N-methyl-N-nitrosourea-induced mammary tumours of Sprague-Dawley rats.

BACKGROUND: Single dose of N-methyl-N-nitrosourea (MNU) was shown to induce malignant tumours in susceptible rat strains. However, such tumours are not well-characterized. MATERIAL AND METHODS: We characterized MNU-induced tumours in Sprague-Dawley rats using ultrasonographic, radiographic and immunohistochemical (IHC) methods. RESULTS: In 27 rats, 41 tumours developed, appearing ultrasonographically as hypodense, non-homogenic areas with signal enhancement at their periphery. Out of these, 39 were of malignant epithelial origin, with an IHC phenotype closely-resembling that of human invasive ductal breast carcinoma. One case was diagnosed as carcinosarcoma. IHC analysis revealed that Ki-67 antigen expression correlated positively with tumour volume (r=0.40, p=0.0079). Moreover, tumours with α-smooth muscle actin in the tumour stroma were characterized by a higher proliferative rate as compared to those without its expression (p<0.05). CONCLUSION: This rat model of chemical carcinogenesis may be suitable for examining breast cancer development and progression.

Long-term statin use and risk of ductal and lobular breast cancer among women 55 to 74 years of age.

BACKGROUND: Mechanistic studies largely support the chemopreventive potential of statins. However, results of epidemiologic studies investigating statin use and breast cancer risk have been inconsistent and lacked the ability to evaluate long-term statin use. METHODS: We used data from a population-based case-control study of breast cancer conducted in the Seattle-Puget Sound region to investigate the relationship between long-term statin use and breast cancer risk. Nine hundred sixteen invasive ductal carcinoma (IDC) and 1,068 invasive lobular carcinoma (ILC) cases in patients 55 to 74 years of age diagnosed between 2000 and 2008 were compared with 902 control women. All participants were interviewed in-person and data on hypercholesterolemia and all episodes of lipid-lowering medication use were collected through a structured questionnaire. We assessed the relationship between statin use and IDC and ILC risk using polytomous logistic regression. RESULTS: Current users of statins for 10 years or longer had a 1.83-fold increased risk of IDC [95% confidence interval (CI): 1.14-2.93] and a 1.97-fold increased risk of ILC (95% CI: 1.25-3.12) compared with never users of statins. Among women diagnosed with hypercholesterolemia, current users of statins for 10 years or longer had more than double the risk of both IDC (OR: 2.04, 95% CI: 1.17-3.57) and ILC (OR: 2.43, 95% CI: 1.40-4.21) compared with never users. CONCLUSION: In this contemporary population-based case-control study, long-term use of statins was associated with increased risks of both IDC and ILC. IMPACT: Additional studies with similarly high frequencies of statin use for various durations are needed to confirm this novel finding.

Estrogen plus progestin and breast cancer incidence and mortality in the Women's Health Initiative Observational Study.

BACKGROUND: In the Women's Health Initiative (WHI) randomized trial, estrogen plus progestin increased both breast cancer incidence and mortality. In contrast, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers. To address differences, a cohort of WHI observational study participants with characteristics similar to the WHI clinical trial was studied. METHODS: We identified 41 449 postmenopausal women with no prior hysterectomy and mammogram negative within 2 years who were either not hormone users (n = 25 328) or estrogen and progestin users (n = 16 121). Multivariable-adjusted Cox proportional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). All statistical tests were two-sided. RESULTS: After a mean of 11.3 (SD = 3.1) years, with 2236 breast cancers, incidence was higher in estrogen plus progestin users than in nonusers (0.60% vs 0.42%, annualized rate, respectively; HR = 1.55, 95% CI = 1.41 to 1.70, P < .001). Women initiating hormone therapy closer to menopause had higher breast cancer risk with linear diminishing influence as time from menopause increased (P < .001). Survival after breast cancer, measured from diagnosis, was similar in combined hormone therapy users and nonusers (HR = 1.03, 95% CI = 0.79 to 1.35). On a population basis, there were somewhat more deaths from breast cancer, measured from cohort entry (HR = 1.32, 95% CI = 0.90 to 1.93, P = .15), and more all-cause deaths after breast cancer (HR = 1.65, 95% CI = 1.29 to 2.12, P < .001) in estrogen plus progestin users than in nonusers. CONCLUSIONS: Consistent with WHI randomized trial findings, estrogen plus progestin use is associated with increased breast cancer incidence. Because prognosis after diagnosis on combined hormone therapy is similar to that of nonusers, increased breast cancer mortality can be expected.

A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication.

Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10(-6) for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10(-7)) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.

Dehydroepiandrosterone intake protects against 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in the obese Zucker rat model.

Obesity has been epidemic in the US for over two decades; almost 65% of adults in the US are overweight. Obesity has been linked with the risk of development of various cancers, including breast cancer. Dehydroepiandrosterone (DHEA) is an over-the-counter dietary supplement used as an immunomodulating, anti-depressant, anti-aging, anti-cardiovascular disease, and anti-cancer agent and anti-obesity supplement. The objectives of this study were to investigate the long-term effects of obesity and DHEA treatment on body weight gain and on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor development. Forty-three six-week-old obese female Zucker rats were used. Rats were randomly assigned and had ad libitum access to water and a diet of either chow (2016) as a control diet or chow with the addition of DHEA at a concentration of 6 g/kg of chow as a DHEA diet. All rats were orally gavaged at age 50 days with 65 mg DMBA/kg body weight. Rats were weighed and palpated twice weekly for detection of mammary tumors and sacrificed 155 days post-DMBA treatment. Obese rats fed the DHEA diet gained significantly less weight than obese control diet rats (P<0.001). At the end of the experiment, 55% of the control diet group developed mammary tumors, while no tumors were detected in the DHEA diet group (P<0.001). Our results suggest that DHEA treatment can reduce body weight gain and protects against DMBA-induced mammary tumor development in the obese Zucker rat model.

Estrogen therapy and risk of breast cancer in postmenopausal women: a case-control study and results of a multivariate analysis.

OBJECTIVE: Several randomized trials and observational studies show that the use of hormone therapy (HT) increases the risk of breast cancer (BC). The aim of this study was to assess the effects of exposure to both HT and oral contraceptives (OCs) on BC risk in postmenopausal women, all residing in the same metropolitan area. METHODS: Data regarding a series of 238 consecutive postmenopausal women with infiltrating ductal carcinoma (cases) and 255 randomly selected age-matched healthy women (controls) were reviewed. Odds ratios for no breast-feeding and HT and OC use were 1.82 (95% CI, 1.20-2.77), 2.49 (95% CI, 1.73-3.58), and 2.06 (95% CI 1.14-3.70), respectively. RESULTS: Four independent variables (years between menarche and menopause, breast-feeding, OC use, and HT use) were included in the final multivariate analysis using logistic regression. The cumulative odds ratio calculated from the observed versus predicted values, obtained using the logistic regression function, was 4.55 (95% CI, 2.13-9.71), whereas the cumulative risk of common exposure to both OCs and HT was 2.77 (95% CI, 1.44-5.32). The logistic model correctly classified 67.5% (95% CI, 63.2-71.5) of cases. The receiver operating characteristic (ROC) curve of the complete logistic function showed a fair area of accuracy (0.77; 95% CI, 0.72-0.81). CONCLUSIONS: Our results show that the risk of common exposure to both OCs and HT increases in women with other risk factors. However, several parameters traditionally considered in epidemiological studies do not have the same weight in each local community, suggesting the need to create different models to correctly select the high-risk population.

Specific overexpression of cyclin E·CDK2 in early preinvasive and primary breast tumors in female ACI rats induced by estrogen.

Overexpressed Aurora A, amplified centrosomes, and aneuploidy are salient features of estrogen-induced mammary preinvasive lesions and tumors in female August--Copenhagen Irish (ACI) rats. Intimately involved in these events are cyclins and their associated cyclin-dependent kinase (CDK) partners. Cyclin E1·CDK2 overexpression plays an important dual role in late G1/S phase of the cell cycle in cancer cells. It increases DNA replication providing growth advantage to cancer cells and facilitates aberrant centrosome duplication, generating chromosomal instability and aneuploidy leading to tumor development. Presented herein, a 24.0- and 45.0-fold elevation in cyclin E1 and CDK2 was found in 17ß-estradiol (E(2))-induced ACI rat mammary tumors (MTs), respectively. Cyclin E·CDK2 positive staining was confined to the large round cells found within focal dysplasias, ductal carcinomas in situ, and invasive MTs. Co-immunoprecipitation and in vitro kinase activity of these tumors revealed that these cell cycle entities are functional. When mammary tissue derived from untreated normal, E(2)-induced hyperplasia and primary tumors were normalized to cyclin E1 levels, low molecular weight (LMW) cyclin E1 forms (33- and 45-kDa) were detected in all of these tissue groups. Moreover, increasing concentrations of protease inhibitor in tissue lysates resulted in a marked reduction of LMW forms, indicating that the presence of cyclin E1 LMW forms can be markedly reduced. Significant increases in cyclin E1 mRNA (2.1-fold) were detected in primary ACI rat E(2)-induced breast tumors, and quantitative real-time polymerase chain reaction revealed a 20% amplification of the cyclin E1 gene (CCNE1). Collectively, these results support the involvement of cyclin E1·CDK2 in centrosome overduplication during each stage of E(2)-induced mammary tumorigenesis.