Breast cancer risk factors among Mexican-American women

Introduction: The average age of onset of breast cancer among Hispanic women is 50 years, more than a decade earlier than non-Hispanic white women. Age at diagnosis is an important prognostic factor for breast cancer; younger age at onset is more likely to be associated with advanced disease, poorer prognosis, hormone receptor negative breast tumors, and a greater likelihood of hereditary breast cancer. Studies of breast cancer risk factors including reproductive risk factors, family history of breast cancer, and breast cancer subtype have been conducted predominately in non-Hispanic whites. Breast cancer is a heterogeneous disease with the presence of clinically, biologically, and epidemiologically distinct subtypes that also differ with respect to their risk factors. The associations between reproductive risk factors and family history of breast cancer have been well documented in the literature. However, only a few studies have assessed these associations with breast cancer subtype in Hispanic populations. Methods: To assess the associations between reproductive risk factors and family history of breast cancer we conducted three separate studies. First, we conducted a case-control study of 172 Mexican-American breast cancer cases and 344 age matched controls residing in Harris County, TX to assess reproductive and other risk factors. We conducted logistic regression analysis to assess differences in cases and controls adjusted for age at diagnosis and birthplace and then we conducted a multinomial logistic regression analysis to compare reproductive risk factors among the breast tumor subtypes. In a second study, we identified 139 breast cancer patients with a first- or second-degree family history of breast cancer and 298 without a family history from the ELLA Bi-National Breast Cancer Study. In this analysis, we also computed a multinomial logistic regression to evaluate associations between family history of breast cancer and breast cancer subtypes, and logistic regression to estimate associations between breast cancer screening practices with family history of breast cancer. In the final study, we employed a cross-sectional study design in 7279 Mexican-American women in the Mano a Mano Cohort Study. We evaluated associations with family history of breast cancer and breast cancer risk factors including body mass index (BMI), lifestyle factors, migration history, and adherence to American Cancer Society (ACS) guidelines. Results: In the results of our first analyses, reproductive risk factors differed in the magnitude and direction of associations when stratified by age and birthplace among cases and controls. In our second study, family history of breast cancer, and having at least one relative diagnosed at an early age (<50 years) was associated with triple negative breast cancer (TNBC). Mammography prior to receiving a breast cancer diagnosis was associated with family history of breast cancer. In our third study that assessed lifestyle factors, migration history and family history of breast cancer; we found that women with a first-degree family history of breast cancer were more overweight or obese compared with their counterparts without a family history. There was no indication that having a family history contributed to women practicing healthier lifestyle behaviors and/or adhering to the ACS guidelines for cancer prevention. Conclusions: We observed that among Mexican-American women, reproductive risk factors were associated with breast cancer where the woman was born (US or Mexico). Having a family history of breast cancer, especially having either a first- or second-degree relative diagnosed at a younger age, was strongly associated with TNBC subtype. These results are consistent with other published studies in this area. Further, our results indicate that women with strong family histories of breast cancer are more likely to undertake mammography but not to engage in healthier lifestyle behaviors.^

Breast cancer risk and heterocyclic amines and effect modification by NAT gene polymorphisms

Breast cancer is the most common cancer in women in the United States and is a leading cause of cancer-related deaths (1). Recently, dietary heterocyclic amines (HCAs) have been proposed to be a risk factor for breast cancer (2). This study uses the data collected for a case-control study conducted at the M.D. Anderson Cancer Center to assess the association between breast cancer risk and HCAs {2-amino-1-methyl-6-phenylimidazole [4,5-b] pyridine (PhIP), 2-amino-3,8-dimethylimidazo [4,5-f] quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo [4,5-f] quinoxaline (DiMeIQx) and mutagenicity of HCAs} and to examine if this association is modified by genetic polymorphisms of N-acetyl transferases (NAT1/NAT2). The NAT1/2 genotype was determined using Taqman technology. HCAs were estimated by using a meat preparation questionnaire on meat type, cooking method, and doneness, combined with a quantitative HCA database. Three hundred and fifty patients with breast cancer attending the Diagnostic Radiology Clinic at M. D. Anderson Cancer Center and fulfilling the eligibility criteria were compared to three hundred and fifty patients attending the same clinic for benign breast lesions to answer these questions. Logistic regression models were used to control for known risk factors and showed no statistically significant association between breast cancer versus benign breast cancer lesions and dietary intake of heterocyclic amines. There was no clear difference in their effect after subgroup analyses in different acetylator strata of NAT1/2 and no statistical interactions were found between NAT1/2 genotypes and HCAs, suggesting no effect modification by NAT1/2 acetylator status. These results suggest the need for further research to analyze if these null associations were because of the benign breast lesions sharing the risk factors with breast cancer or any other factors which haven't been explored yet.^

Validity assessment of the Breast Cancer Risk Reduction Health Belief scale.

BACKGROUND: : Women at increased risk of breast cancer (BC) are not widely accepting of chemopreventive interventions, and ethnic minorities are underrepresented in related trials. Furthermore, there is no validated instrument to assess the health-seeking behavior of these women with respect to these interventions. METHODS: : By using constructs from the Health Belief Model, the authors developed and refined, based on pilot data, the Breast Cancer Risk Reduction Health Belief (BCRRHB) scale using a population of 265 women at increased risk of BC who were largely medically underserved, of low socioeconomic status (SES), and ethnic minorities. Construct validity was assessed using principal components analysis with oblique rotation to extract factors, and generate and interpret summary scales. Internal consistency was determined using Cronbach alpha coefficients. RESULTS: : Test-retest reliability for the pilot and final data was calculated to be r = 0.85. Principal components analysis yielded 16 components that explained 64% of the total variance, with communalities ranging from 0.50-0.75. Cronbach alpha coefficients for the extracted factors ranged from 0.45-0.77. CONCLUSIONS: : Evidence suggests that the BCRRHB yields reliable and valid data that allows for the identification of barriers and enhancing factors associated with use of breast cancer chemoprevention in the study population. These findings allow for tailoring treatment plans and intervention strategies to the individual. Future research is needed to validate the scale for use in other female populations. Cancer 2009. (c) 2009 American Cancer Society.

Alcohol consumption and breast cancer risk among Hispanic and non-Hispanic women in New Mexico

Breast cancer incidence and mortality rates for Hispanic women are lower than for non-Hispanic white (NHW) women, but recently rates have increased more rapidly among Hispanic women. Many studies have shown a consistent increased breast cancer risk associated with modest or high alcohol intake, but few included Hispanic women. Alcohol consumption and risk of breast cancer was investigated in a New Mexico statewide population-based case-control study. The New Mexico Tumor Registry ascertained women, newly diagnosed with breast cancer (1992–1994) aged 30–74 years. Controls were identified by random digit dialing and were frequency-matched for ethnicity, age-group, and health planning district. In-person interviews of 712 cases and 844 controls were conducted. Data were collected for breast cancer risk factors, including alcohol intake. Recent alcohol intake data was collected for a four-week period, six months prior to interview. Past alcohol intake included information on alcohol consumption at ages 25, 35, and 50. History of alcohol consumption was reported by 81% of cases and 85% of controls. Of these women, 42% of cases and 48% of controls reported recent alcohol intake. Results for past alcohol intake did not show any trend with breast cancer risk, and were nonsignificant. Multivariate-adjusted odds ratios for recent alcohol intake and breast cancer suggested an increased risk at the highest level for both ethnic groups, but estimates were unstable and statistically nonsignificant. Low level of recent alcohol intake (<148 grams/week) was associated with a reduced risk for NHW women (Odds Ratio (OR) = 0.49 95% Confidence Interval (CI) 0.35–0.69). This pattern was independent of hormone-receptor status. The reduced breast cancer risk for low alcohol intake was present for premenopausal (OR = 0.29, 95% CI 0.15–0.56) and postmenopausal NHW women (OR = 0.56, 95% CI 0.35–0.90). The possibility of an increased risk associated with high alcohol intake could not be adequately addressed, because there were few drinkers with more than light to moderate intake, especially among Hispanic women. An alcohol-estrogen link is hypothesized to be the mechanism responsible for increased breast cancer risk, but has not been consistently substantiated. More studies are needed of the underlying mechanism for an association between alcohol intake and breast cancer. ^

The role of self-efficacy in a low fat high fiber intervention to reduce breast cancer risk among African American women

Purpose. To determine if self-efficacy (SE) changes predicted total fat (TF) and total fiber (TFB) intake and the relationship between SE changes and the two dietary outcomes. ^ Design. This is a secondary analysis, utilizing baseline and first follow up (FFU) data from the NULIFE, a randomized trial. ^ Setting. Nutrition classes were taught in the Texas Medical Center in Houston, Texas. ^ Participants. 79 pre-menopausal, 25--45 year old African American women with an 85% response rate at FFU. ^ Method. Dietary intake was assessed with the Arizona Food Frequency Questionnaire and SE with the Self Efficacy for Dietary Change Questionnaire. Analysis was done using Stata version 9. Linear and logistic regression was used with adjustment for confounders. ^ Results. Linear regression analyses showed that SE changes for eating fruits and vegetables predicted total fiber intake in the control group for both the univariate (P = 0.001) and multivariate (P = 0.01) models while SE for eating fruits and vegetables at first follow-up predicted total fiber intake in the intervention for both models (P = 0.000). Logistic regression analyses of low fat SE changes and 30% or less for total fat intake, showed an adjusted OR of 0.22 (95% CI = 0.03, 1.48; P = 0.12) in the intervention group. The logistic regression analyses of SE changes in fruits and vegetables and 10g or more for total fiber intake, showed an adjusted OR of 6.25 (95% CI = 0.53, 72.78; P = 0.14) in the control group. ^ Conclusion. SE for eating fruits and vegetables at first follow-up predicted intervention groups' TFB intake and intervention women that increased their SE for eating a low fat diet were more likely to achieve the study goal of 30% or less calories from TF. SE changes for eating fruits and vegetables predicted the control's TFB intake and control women that increased their SE for eating fruits and vegetables were more likely to achieve the study goal of 10 g or more from TFB. Limitations are use of self-report measures, small sample size, and possible control group contamination.^

Breast cancer risk with aromatase inhibition and phytoestrogen-free diet

In this thesis a mouse model was used to examine the effect of pubertal estrogen inhibition and a phytoestrogen-free diet on the development of mammary glands. The study question was does treatment with aromatase inhibitor during puberty increase susceptibility to breast cancer among cohorts that consumed a diet free of phytoestrogens. The study design consisted of a cohort of mice treated with aromatase inhibitor, letrozole, during puberty and a vehicular group that was used as a control. Both groups were fed a diet free of phytoestrogens from the time of weaning until sacrifice during adulthood. The study aimed to assess mammary gland development in terms of breast cancer risk. The methods employed in this research included morphological and histological analysis of mammary glands, as well as estradiol, RNA and protein analysis. The main finding of the study was that mice exposed to aromatase inhibitor during puberty developed mammary glands with specific characteristics suggestive of vulnerability to oncogenesis such as increased lateral branching, increased number of glands, increase ductal hyperplasia, and diminished expression of TGFβ and p27 protein levels. The conclusions suggest that puberty is a critical period in which the mammary gland is susceptible to environmental threats that may result in deleterious epigenetic effects leading to an increased breast cancer risk in adulthood. This study has several public health implications; the most significant is that environmental threats during puberty may result in adverse mammary gland development and that phytoestrogen sources in the diet are necessary for normal maturation of the mammary glands.^

Risk factors for inflammatory breast cancer

Background: Inflammatory breast cancer (IBC) is rare and accounts for 2.5% of all invasive breast cancers. The 5-year survival rates are significantly lower than for other types of breast cancer, highlighting the significance of cancer prevention in IBC. The comprehensive multi-disciplinary team Morgan Welch Inflammatory Breast Cancer Research Program and Clinic at University of Texas MD Anderson Cancer Center treats the largest number of Inflammatory Breast patients in a single center. Because of this unique center, large patient resources, and good medical and epidemiological records, we were able to conduct the largest single center case-control and case-case study on IBC. Methods: We identified 246 patients diagnosed with IBC and 397 cancer free patients seen at the Dan L Duncan Cancer Prevention Clinic. Breast cancer reproductive risk factors and lifestyle risk factors were compared between tumor subtypes of IBC patients (Estrogen Receptor positive (ER+) and/or Progesterone Receptor positive (PR+), Human Epidermal Growth Factor 2 positive (HER2+)), and (ER -/PR-/HER2-)) and cancer free controls. Results: Breastfeeding was the only significant risk factor (p<0.01) between tumor subtypes in IBC patients. In the case-control study that included all IBC patients and cancer free patients the descriptive statistics indicate significant difference in BMI, history of smoking, number of children, age of first pregnancy, any breastfeeding and total time breastfeeding (p<0.05). No differences were found in the frequency of other breast cancer risk factors. Conclusion: The associations determined between cancer free controls and IBC patients have identified previously unknown risk factors for IBC. The risk factors identified by the case control study suggest BMI, history of smoking, and the protective effect of breastfeeding as potential modifiable risk factors that can be used to decrease the incidence of IBC. Impact: These results highlight the importance of evaluating epidemiologic risk factors of IBC, which could lead to the identification of distinct etiologic pathways that could be targeted for prevention.^

Lifetime changes in body mass index and risk of breast cancer in minority women

Introduction: Obesity is an epidemic in the United States, especially among Hispanics and African-Americans. Studies of obesity and breast cancer risk and subtype have been conducted primarily in non-Hispanic whites. Obesity is inversely associated with premenopausal breast cancer, but both obesity and weight gain increase the risk of postmenopausal disease. Obesity has been associated with breast cancer subtype in many studies. Methods: To assess the association between changes in body mass index (BMI) over the lifetime, weight gain, and breast cancer in Mexican-American women, we conducted a case-control study using 149 cases and 330 age-matched controls. In a second study, we identified 212 African-American and 167 Mexican-American women with breast cancer in the ongoing ELLA Bi-National Breast Cancer Study, abstracted medical charts to classify tumors as ER+/PR+, HER2+, or ER-/PR-/HER2-, and assessed the association between lifetime changes in body mass index, weight gain, and breast cancer subtype. In both studies, growth mixture modeling was use to identify trajectories of change in BMI over the lifetime, and these trajectories were used as exposures in a logistic regression model to calculate odds ratios (OR). Results: There was no association between trajectories of change in BMI and breast cancer risk in Mexican-American women. In addition, BMI at ages 15 and 30 and at diagnosis was not associated with breast cancer. However, adult weight gain was inversely associated with breast cancer risk (per 5kg, OR=0.92, 95% CI: 0.85-0.99). The case-only analysis found no association between obesity at ages 15 and 30 and at diagnosis and breast cancer subtype. Further, there was no association between adult weight gain (defined as weight change from age 15 to time of diagnosis) and breast cancer subtype. Conclusions: Obesity was not associated with breast cancer risk in Mexican-American women, while adult weight gain reduced the risk independently of menopausal status. These results are contradictory of those in non-Hispanic white women and suggest that the etiology of breast cancer may differ by race/ethnicity. Further, obesity was not associated with breast cancer subtype in African-American and Mexican-American women, contrary to results in non-Hispanic white women. ^

DIETARY RELATIONSHIPS TO FATAL BREAST CANCER AMONG SEVENTH-DAY ADVENTISTS

Laboratory experiments in animals, correlational and migrant studies in humans suggest a role for diet in the etiology of breast cancer. Data gathered from individuals via case-control studies are less consistent. Seventh-day Adventist women experience lower mortality from breast cancer than comparable U.S. populations and this decrease is thought to be, at least in part, related to dietary practices (half are vegetarian). In 1960, 25,000 California Seventh-day Adventists completed a questionnaire which included a 21 item food frequency section. Cancer mortality in this population was monitored between 1960 and 1980 and the relationship of high fat food intake and fatal breast cancer was evaluated. Although established risk factors for breast cancer were observed in this population (e.g. age at menarche, age at first pregnancy, age at menopause and obesity) consumption of high fat foods were not observed to exert a strong influence on fatal breast cancer risk. Odds ratios (O.R.) for fatal breast cancer among non-vegetarians was 1.2. Increasing meat consumption bore little relation to risk; O.R. = 1.0, 1.2, 1.1 for consumption categories of none/occasional, 1-3 days/week and 4+ days/week respectively. Nor did the consumption of other high fat foods of animal origin (e.g. butter, cheese, milk, eggs) show any relationship to risk. These results remained unchanged after simultaneously controlling for the effect of other, potentially confounding variables (menstrual characteristics, obesity) via logistic regression analysis. ^

Tumors in the contralateral breast following radiation therapy for breast cancer

The proportional distribution of independent malignant tumors in the contralateral breast following treatment for breast cancer was investigated to assess the influence of scattered radiation as a cause of these tumors. In a population of 172 patients the proportion of contralateral tumors in each quadrant and the center (the nipple-areolar complex) was compared with the expected, or natural, distribution found in the general population, in the absence of radiation. The observed/expected ratio for contralateral tumors was 1.43 for the upper-inner quadrant; 0.97, lower-inner quadrant; 1.51, center; 0.76, upper-outer quadrant; and 0.64, lower-outer quadrant. In each quadrant, except the lower-inner, the observed/expected ratio differed from 1.00 with statistical significance at the 5% level (one-tail). The same analysis, stratified by age and menopausal status, showed a similar shift of tumors, with more than expected in the inner quadrants and center and less than expected in the outer quadrants, although the results did not show statistical significance at the 5% level for all strata. For each patient the mean absorbed radiation dose for each quadrant and center of the breast was estimated, based on measurements in a tissue-equivalent phantom. Among patients the doses ranged from 0.5 to 8 Gy; within individuals, doses to the inner quadrants typically were a factor of three times higher than doses to the outer quadrants. The results suggest that radiation may be a risk factor for contralateral breast tumors and warrants further investigation. ^

A case-control study of bilateral compared with unilateral breast cancer

Approximately 10 to 15% of breast cancer patients develop a primary cancer in the contralateral breast. This study examined differences between women with unilateral compared with bilateral primary breast cancer. It focused on hormonal factors and family history, and evaluated the prevalences of invasive lobular histology and the replication error phenotype in the tumors. ^ Cases (n = 82) were patients at M.D. Anderson Cancer Center (MDACC) in Houston, Texas diagnosed with primary breast cancer in each breast between 1985 and 1994 inclusive. Controls (n = 82) were MDACC patients with primary cancer in a single breast diagnosed during the same interval, individually matched to cases. Data were obtained by in-person and/or telephone interview with the patient and/or proxy. Replication error phenotype was determined from archival tissue. ^ Diagnosis of breast, but not ovarian, cancer in a female first-degree relative (FFDR) was a strong risk factor for bilateral cancers. Cases had a significantly 3-fold higher excess of familial breast cancer than did controls (cases: O/E = 2.65, 95% CI = 1.85–3.69; controls: 0.86, 0.46–1.47; homogeneity: p = 0.00). Risk did not vary with menopausal status of the patient, but was greatest if a relative was diagnosed before age 45 (O/E = 38.9; 95% CI = 21.7–64.1). By implication, young first-degree relatives of patients with bilateral breast cancer are at very high risk of breast cancer themselves. Cases also had significantly fewer siblings than did controls. ^ Earlier menarche, and parity in the absence of lactation, were associated with bilateral cancers; age at menopause and parity with lactation were not. A history of alcohol consumption, particularly if heavy, carried a 3.4-fold risk (p = 0.03). The data suggested a slightly different pattern in risk factors according to menopausal status and interval between cancers. ^ Replication error phenotype was available for 59 probands. It was associated with bilateral cancers (particularly if diagnosed within one year of each other), increased age (p = 0.02) and negative nodal status. Invasive lobular histology was associated with bilateral disease but numbers were small. ^ These data suggest bilateral breast cancer arises in the context of a combination of familial and hormonal factors, and alcohol consumption. The relative importance of each factor may vary by age of the patient. ^

Primary lung cancer after breast cancer: The role of radiation therapy and cigarette smoking

The magnitude of the interaction between cigarette smoking, radiation therapy, and primary lung cancer after breast cancer remains unresolved. This case control study further examines the main and joint effects of cigarette smoking and radiation therapy (XRT) among breast cancer patients who subsequently developed primary lung cancer, at The University of Texas M. D. Anderson Cancer Center (MDACC) in Houston, Texas. Cases (n = 280) were women diagnosed with primary lung cancer between 1955 and 1970, between 30–89 years of age, who had a prior history of breast cancer, and were U.S. residents. Controls (n = 300) were randomly selected from 37,000 breast cancer patients at MDACC and frequency matched to cases on age at diagnosis (in 5-year strata), ethnicity, year of breast cancer diagnosis (in 5-year strata), and had survived at least as long as the time interval for lung cancer diagnosis in the cases. Stratified analysis and unconditional logistic regression modeling were used to calculate the main and joint effects of cigarette smoking and radiation treatment on lung cancer risk. Medical record review yielded smoking information on 93% of cases and 84% of controls, and among cases 45% received XRT versus 44% of controls. Smoking increased the odds of lung cancer in women who did not receive XRT (OR = 6.0, 95%CI, 3.5–10.1) whereas XRT was not associated with increased odds (OR = 0.5, 95%CI, 0.2–1.1) in women who did not smoke. Overall the odds ratio for both XRT and smoking together compared with neither exposure was 9.00 (9 5% CI, 5.1–15.9). Similarly, when stratifying on laterality of the lung cancer in relation to the breast cancer, and when the time interval between breast and lung cancers was >10 years, there was an increased odds for both smoking and XRT together for lung cancers on the same side as the breast cancer (ipsilateral) (OR = 11.5, 95% CI, 4.9–27.8) and lung cancers on the opposite side of the breast cancer (contralateral) (OR= 9.6, 95% CI, 2.9–0.9). After 20 years the odds for the ipsilateral lung were even more pronounced (OR = 19.2, 95% CI, 4.2–88.4) compared to the contralateral lung (OR = 2.6, 95% CI, 0.2–2.1). In conclusion, smoking was a significant independent risk factor for lung cancer after breast cancer. Moreover, a greater than multiplicative effect was observed with smoking and XRT combined being especially evident after 10 years for both the ipsilateral and contralateral lung and after 20 years for the ipsilateral lung. ^

Clinical relevance of polymorphic DNA copy number variation (CNV) in African American women with stage I-II breast cancer

Objectives. The chief goal of this study was to analyze copy number variation (CNV) in breast cancer tumors from 25 African American women with early stage breast cancer (BC) using molecular inversion probes (MIP) in order to: (1) compare the degree of CNV in tumors compared to normal lymph nodes, and (2) determine whether gains and/or losses of genes in specific chromosomes differ between pathologic subtypes of breast cancer defined by known prognostic markers, (3) determine whether gains/losses in CN are associated with known oncogenes or tumor suppressor genes, and (4) determine whether increased gains/losses in CN for specific chromosomes were associated with differences in breast cancer recurrence. ^ Methods. Twenty to 37 nanograms of DNA extracted from 25 formalin-fixed paraffin embedded (FFPE) tumor samples and matched normal lymph nodes were added to individual tubes. Oligonucleotide probes with recognition sequences at each terminus were hybridized with a genomic target sequence to form a circular structure. Probes are released from genomic DNA obtained from FFPE samples, and those which have been correctly "circularized" in the proper allele/nucleotide reaction combination are amplified using polymerase chain reaction (PCR) primers. Amplicons were fluorescently labeled and the tag sequences released from the genome homology regions by treatment with uracil-N-glycosylase to cleave the probe at the site where uracils are present, and detected using a complementary tag array developed by Affymetrix. ^ Results. Analysis of CN gains and losses from tumors and normal tissues showed marked differences in tumors with numerous chromosomes affected. Similar changes were not observed in normal lymph nodes. When tumors were stratified into four groups based on expression or lack of expression of the estrogen receptor and HER2/neu, distinct patterns of CNV for different chromosomes were observed. Gains or losses in CN for specific chromosomes correlated with amplifications/deletions of particular oncogenes or tumor suppressor genes (i.e. such as found on chromosome 17) known to be associated with aggressive tumor phenotype and poor prognosis. There was a trend for increases in CN observed for chromosome 17 to correlate inversely with time to recurrence of BC (p=0.14 for trend). CNV was also observed for chromosomes 5, 8, 10, 11, and 16, which are known sites for several breast cancer susceptibility alleles. ^ Conclusions. This study is the first to validate the MIP technique, to correlate differences in gene expression with known prognostic tumor markers, and to correlate significant increases/decreases in CN with known tumor markers associated with prognosis. The results of this study may have far reaching public health implications towards identifying new high-risk groups based on genomic differences in CNP, both with respect to prognosis and response to therapy, and to eventually identify new therapeutic targets for prevention and treatment of this disease. ^

Role of IkappaB kinase beta in inflammation-mediated breast cancer development

Breast cancer is the second most common farm of cancers and the second leading cause of cancer death for American women. Clinical studies indicate inflammation is a risk factor for breast cancer development. Among the cytokines and chemokines secreted by the infiltrating inflammatory cells, tumor necrosis factor a (TNFα) is considered one of the most important inflammatory factors involved in inflammation-mediated tumorigenesis. ^ Here we found that TNFα/IKKβ signaling pathway is able to increase tumor angiogenesis through activation of mTOR pathway. While investigating which molecule in the mTOR pathway involved in TNFα/IKKβ-mediated mTOR activation, our results showed that IKKβ physically interacts with and phosphorylates TSC1 at Ser487 and Ser511 in vitro and in vivo. Phosphorylation of TSC1 by IKKβ inhibits its association with TSC2, alters TSC2 membrane localization, and thereby activates mTOR. In vitro angiogenesis assays and orthotopic breast cancer model reveals that phosphorylation of TSC1 by IKKβ enhances VEGF expression, angiogenesis and culminates in tumorigenesis. Furthermore, expression of activated IKKβ is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. ^ Furthermore, dysregulation of tumor suppressor FOXO3a contributes to the development of breast cancer. We found that overexpression of IKKβ led to inhibition of FOXO3a-mediated transactivation activity. While investigating the underlying mechanisms of IKKβ-mediated dysregulation of FOXO3a, our results showed that IKKβ physically associated with FOXO3a and phosphorylated FOXO3a at Ser644 in vitro and in vivo. The phosphorylation of FOXO3a by IKKβ altered its subcellular localization from nucleus to cytoplasm and promoted its degradation through ubiquitin-proteasome pathway. Mutation of FOXO3a at Ser644 prevented IKKβ-induced ubiquitination and degradation. In vitro cell proliferation assay and orthotopic breast cancer model revealed that phosphorylation of FOXO3a by IKKβ overrode FOXO3a-mediated repression of tumor progression. ^ In conclusion, our findings identify IKKβ-mediated suppressions of both TSC1 and FOXO3a are critical for inflammation-mediated breast cancer development through increasing tumor angiogenesis and evading apoptosis, respectively. Understanding the role of IKKβ in both FOXO3a and TSC/mTOR signaling pathways provides a critical insight of inflammation-mediated diseases and may provide a target for clinical intervention in human breast cancer. ^

Anesthetic choices and breast cancer recurrence: A retrospective cohort study of risk factors

Background: The impact of anesthetic techniques for breast cancer surgery traditionally has been centered on the incidence of acute pain syndromes and complications immediately after surgery. Evaluating anesthesia management beyond short-term effects is an emerging science. Several animal studies have concluded that regional anesthesia independently reduces cancer recurrence and metastasis. A small number of retrospective clinical studies indicate that reductions in cancer recurrence are attributable to anesthesia technique; however, individual risk factors need to be taken into consideration. ^ Purpose: The aims were to: 1) investigate differences in patient, disease and treatment factors between women who received surgical treatment for breast cancer with paravertebral regional and general anesthesia compared to women who received general anesthesia alone; 2) explore patient, disease and treatment factors associated with recurrence of breast cancer; and 3) test the association between type of anesthesia and breast cancer recurrence and survival over 22–46 months following surgery. ^ Methods: This retrospective cohort study included 358 patients with stage 0-III disease who received a partial or total mastectomy without axillary node dissection between October 2006 and October 2008 at a large academic cancer center. Follow-up ended in August 2010 with a median follow-up time of 28.8 months. ^ Results: The patient demographics were equally represented across anesthesia groups. Mean BMI (kg/m2) was greater for the patients who received general anesthesia (GA) alone (29±6.8) compared to those that received paravertebral regional block (PVB) with GA (28±5.1), p=0.001. The PVB with GA group had more advanced stages of disease (p=0.01) and longer surgeries (p=0.01) than the GA only group. Breast cancer recurrence was detected in only 1.7% of the study population. The mean age was 51±18 in those who had a recurrence compared to 58±11 in the non-recurrent group (p=0.06). Overall, no association between anesthesia type and recurrence was found (p=0.53), with an unadjusted estimated hazard ratio of 1.84 (95% CI 0.34–10.08). ^ Conclusions: In contrast to previous retrospective studies in cancer patients receiving surgical and anesthesia treatment, this study was unable to detect a difference in relating type of anesthesia with decreased breast cancer recurrence. Nonetheless, a significant association between BMI and type of anesthesia was observed and should be taken into account in future studies. Because the overall rate of recurrence was very small in this population, a larger study would be needed to detect any differences in rates of recurrence attributable to type of anesthesia. ^