Association of genetic polymorphisms of <Emphasis Type="Italic">ER-α</Emphasis> and the estradiol-synthesizing enzyme genes <Emphasis Type="Italic">CYP17</Emphasis> and <Emphasis Type="Italic">CYP19</Emphasis> with breast cancer risk in Chinese women

Estrogen plays a role in breast cancer development, and genetic polymorphisms in estrogen receptor gene ER-α and genes regulating estrogen biosynthesis and metabolisms are associated with the risk of breast cancer in women in western countries. Therefore, we hypothesized that SNPs in ER-α and other estrogen-metabolizing genes contribute to breast cancer risk in Chinese women. In this study, we genotyped polymorphisms in the regulatory regions of ER-α (rs3798577) and other two estrogen-metabolizing enzyme genes CYP17 (rs743572) and CYP19 (rs10046) among 300 breast cancer cases and 390 controls in a Chinese population. Crude and adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses to estimate breast cancer risk associated with these polymorphisms. We found that the T allele frequency of ER-α was significantly higher in cases (59.8%) than controls (54.5%) (P = 0.047), but no significant difference was found in the genotype distribution. However, postmenopausal breast cancer risk was associated with the CYP17 TC genotype (aOR = 1.77, 95% CI = 1.11–2.83) compared with the TT genotype. The CYP19 variant TC + TT genotypes were associated with both overall cancer risk (TT + TC vs. TT aOR = 1.73, 95% CI = 1.13–2.65) and premenopausal cancer risk (TT + TC vs. TT aOR = 1.78, 95% CI = 1.03–3.09), particularly for ER +/PR + tumors. Furthermore, there were joint effects between CYP19 T and ER-α T varint genotypes (aOR = 1.67, 95% CI = 1.03–2.69 for CYP19 TC + TT vs. CC among ER-α T variant carriers) and between CYP19 T and CYP17 C variant genotypes (aOR = 1.77, 95% CI = 1.11–2.83 for CYP19 TC + TT vs. CC among CYP17 variant C carriers). This study provides evidence that polymorphisms CYP17 rs743572, CYP19 rs10046 and ER-α rs3798577 are associated with breast cancer risk among Chinese women.     

Polymorphisms of the DNA polymerase <Emphasis Type="Italic">β</Emphasis> gene in breast cancer

DNA polymerase β (Polβ) provides most of the gap-filling synthesis at apurinic/apyrimidine sites of damaged DNA in the base excision repair pathway. Mutations in the gene encoding DNA polβ have been identified in various carcinomas. We performed a case–control study to test the association between two polymorphisms in the polβ gene: a Pro → Arg change at codon 242 (the Pro242Arg polymorphism) and a Lys → Met change at codon 289 (the Lys289Met polymorphism) and breast cancer risk and cancer progression. Genotypes were determined in DNA from peripheral blood lymphocytes of 150 breast cancer patients and 150 cancer-free, age-matched women (controls) by PCR-RFLP. A strong association between breast cancer occurrence and the Met/Met phenotype of the Lys289Met polymorphism [odds ratio (OR) 3.67; 95% confidence interval (CI) 1.87–7.56] and the Pro/Arg phenotype of the Pro242Lys polymorphism (OR 1.96; 95% CI 1.15–3.34) was found. Polymorphism–polymorphism interaction between the Met/Met phenotype of the Lys289Met and the Pro/Arg phenotype of the Pro242Arg variants increased the risk of breast cancer (OR 3.05; 95% CI 1.31–7.09). We did not observe any correlation between studied polymorphisms and breast cancer progression evaluated by node-metastasis, tumor size and Bloom–Richardson grading. In conclusion, Polβ may play a role in the breast carcinogenesis and the Lys289Met polymorphism of the polβ gene may be considered as an independent, early, molecular diagnostic marker in breast cancer. The Pro242Arg polymorphism may contribute to the carcinogenesis through the interaction with the Lys289Met and therefore may be regarded as a dependent, auxiliary marker.     

<Emphasis Type="Italic">Estrogen receptor</Emphasis> α, <Emphasis Type="Italic">BRCA1</Emphasis>, and <Emphasis Type="Italic">FANCF</Emphasis> promoter methylation occur in distinct subsets of sporadic breast cancers

Introduction Alcohol intake has been consistently associated with breast cancer risk, but the importance of timing of intake and the impact of beverage type are unclear. Methods We evaluated whether early, lifetime or recent alcohol intake was associated with breast cancer risk, and whether risk varied by type of alcoholic drinks in 1,728 newly diagnosed population-based breast cancer patients and 435 control subjects aged 20–49 years. We used multivariable logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) as measures of the relative risk of breast cancer associated with intake of alcoholic drinks. Results Intake of alcoholic drinks during the recent five year period before the breast cancer diagnosis was associated with increased breast cancer risk (P _trend = 0.04). Intake of two or more alcoholic drinks per day during this five year period was associated with an 82% increase in breast cancer risk relative to never drinkers (OR = 1.82, 95% CI = 1.01–3.28). No risk increase was observed for alcohol intake at ages 15–20 years or for lifetime alcohol intake. Risk did not vary by type of alcohol consumed. Conclusions Our results suggest that recent alcohol consumption may be associated with increased breast cancer risk in young women.     

Smoking and risk of breast cancer in carriers of mutations in <Emphasis Type="Italic">BRCA1</Emphasis> or <Emphasis Type="Italic">BRCA2</Emphasis> aged less than 50 years

Background Cigarette smoke contains compounds that may damage DNA, and the repair of damage may be impaired in women with germline mutations in BRCA1 or BRCA2. However, the effect of cigarette smoking on breast cancer risk in mutation carriers is the subject of conflicting reports. We have examined the relation between smoking and breast cancer risk in non-Hispanic white women under the age of 50 years who carry a deleterious mutation in BRCA1 or BRCA2. Methods We conducted a case-control study using data from carriers of mutations in BRCA1 (195 cases and 302 controls) and BRCA2 (128 cases and 179 controls). Personal information, including smoking history, was collected using a common structured questionnaire by eight recruitment sites in four countries. Odds-ratios (OR) for breast cancer risk according to smoking were adjusted for age, family history, parity, alcohol use, and recruitment site. Results Compared to non-smokers, the OR for risk of breast cancer for women with five or more pack-years of smoking was 2.3 (95% confidence interval 1.6–3.5) for BRCA1 carriers and 2.6 (1.8–3.9) for BRCA2 carriers. Risk increased 7% per pack-year (p < 0.001) in both groups. Conclusions These results indicate that smoking is associated with increased risk of breast cancer before age 50 years in BRCA1 and BRCA2 mutation carriers. If confirmed, they provide a practical way for carriers to reduce their risks. Previous studies in prevalent mutation carriers have not shown smoking to increase risk of breast cancer, but are subject to bias, because smoking decreases survival after breast cancer. Northern California Family Registry for Breast Cancer: AS Whittemore, Stanford University School of Medicine, EM John, Northern California Cancer Center, A Felberg, Stanford University School of Medicine, V McGuire, Stanford University School of Medicine, DW West, Northern California Cancer Center, A Miron, Dana-Farber Cancer Institute, Harvard Medical School, DC Thomas, USC Keck School of Medicine, R Haile, USC Keck School of Medicine and Norris Comprehensive Cancer. Fox Chase Familial Breast Cancer Registry: M Daly, Fox Chase Cancer Center, A Godwin, Fox Chase Cancer Center, E Ross, Fox Chase Cancer Center. Coriell Institute: J Beck. New York Familial Breast Cancer Registry: MB Terry, Joseph L. Mailman School of Public Health, Columbia University. Utah Breast Cancer Family Registry: SS Buys, Huntsman Cancer Institute, V Venne, Huntsman Cancer Institute. Australian Breast Cancer Family Study: JL Hopper, The University of Melbourne, GG Giles, The Cancer Council Victoria, MRE McCredie, University of Otago, New Zealand, RL Milne, Spanish National Cancer Centre, MC Southey, The University of Melbourne, MA Jenkins, The University of Melbourne, C Apicella, The University of Melbourne. Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab), Peter MacCallum Cancer Centre. Ontario Familial Breast Cancer Registry: I Andrulis, Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, NF Boyd, Ontario Cancer Institute, J Knight, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, H Ozcelik, Samuel Lunenfeld Research Institute, Mount Sinai Hospital. Correspondence to: Dr NF Boyd, Campbell Family Institute for Breast Cancer Research, Room 10-415, Ontario Cancer Institute, 610 University Ave., Toronto, Ontario, Canada M5G 2M9. Boyd@uhnres.utoronto.ca     

Prevalence of <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations in unselected breast cancer patients from Medellín,Colombia

Background

Approximately 5% of all breast cancers can be attributed to a mutation in the BRCA1 or BRCA2 gene. The genetic component of breast cancer in Colombia has been, for the most part, studied on cases from the Bogota region. Five different founder mutations have been identified in two studies of breast cancer patients in the Bogota region. It is important that the frequency of mutations be established among unselected cases of breast cancer of other regions of Colombia in order to estimate the genetic burden of this cancer in Colombia and to plan genetic services. The aim of this study was to establish the mutation frequencies of the BRCA genes in breast cancer patients unselected for family history or age, from Medellin, Colombia.

Methods

We enrolled 280 unselected women with breast cancer from a large public hospital in Medellin, Colombia. A detailed family history from each patient and a blood sample was obtained and processed for DNA analysis. Mutations in BRCA1 and BRCA2 were sought using a combination of techniques including a panel of recurrent Hispanic BRCA mutations which consists of fifty BRCA1 mutations and forty-six BRCA2 mutations, including the five recurrent Colombian BRCA mutations. All mutations were confirmed by direct sequencing.

Results

Genetic testing was successfully completed for 244 of the 280 cases (87%). Among the 244 cases, three deleterious mutations were identified (two in BRCA1 and one in BRCA2), representing 1.2% of the total. The average age of breast cancer in the mutation-positive cases was 34 years. The two BRCA1 mutations were known founder mutations (3450del4 in exon 11 and A1708E in exon 18). The BRCA2 mutation was in exon 11 (5844del5) and has not been previously reported in individuals of Colombian descent. Among the three mutation-positive families was a breast cancer family and two families with no history of breast or ovarian cancer.

Conclusion

The frequency of BRCA mutations in unselected breast cancer cases from the Medellin region of Colombia is low and is approximately 1.2%.

     

Relative contributions of <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations to “triple-negative” breast cancer in Ashkenazi Women

Approximately 10% of Ashkenazi Jewish (AJ) women with breast cancer (BC) carry a founder mutation in BRCA1 or BRCA2. There is an association between BRCA1 mutations and “triple-negative” breast cancer (TNBC) [estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 negative]. We sought to determine the predictive value of the TNBC phenotype for the presence of a BRCA mutation in AJ women ascertained without respect to family history. DNA samples were collected between 8/2000 and 6/2004 from a prevalent cohort of unselected AJ women with breast cancer (median age at diagnosis 56 years). Samples (n = 451) were genotyped for AJ founder mutations. 352 (78.0%) cancers were ER positive, 254 (56.3%) PR positive, and 91 (20.2%) ER negative/PR negative. 63 (14.0%) cancers were HER2 positive (immunohistochemistry 3+ or FISH >2.2). TNBC was observed in 64 patients (14.2%). Founder mutations were detected in 48 samples (10.6%) including 25/64 TNBC (39.1%; 19 BRCA1, 6 BRCA2). Among TNBC patients with family history (FH) information, 6/15 (40%) mutations were found in women without breast or ovarian cancer in a close relative. The positive predictive value of TNBC for a BRCA1 mutation was 30% overall, 50% in women diagnosed<50 years, and 14% in women diagnosed ≥50. TNBC was significantly associated with detecting a mutation in either BRCA1 or BRCA2, but only 25/52 (48%) mutation-associated cancers were TNBC. The prevalence of BRCA founder mutations exceeds 50% in subsets of AJ women with TNBC. FH is an imperfect predictor of mutation status in this group. A significant number of mutation-associated TNBC are due to BRCA2.     

Are <Emphasis Type="Italic">BRCA1</Emphasis>- and <Emphasis Type="Italic">BRCA2</Emphasis>-related breast cancers associated with increased mortality?

There has been contradictory evidence as to whether BRCA1 associated breast cancers have a poorer prognosis than non-BRCA1 cancers. In this issue of Breast Cancer Research Robson and colleagues provide further evidence for poorer survival in BRCA1 carriers and show that it could be attributed to failure to treat small node-negative grade 3 breast cancers with chemotherapy. There still remains little evidence for a survival difference for BRCA2 related breast cancers. Although the high contralateral breast cancer risk is confirmed by this study there is no real evidence for an increase in ipsilateral recurrence or new primary breast cancers in mutation carriers up to the 10-year point.     

Association between the <Emphasis Type="Italic">T27C</Emphasis> polymorphism in the <Emphasis Type="Italic">cytochrome P450 c17</Emphasis>α (<Emphasis Type="Italic">CYP17</Emphasis>) gene and risk factors for breast cancer

Mammographic density is associated with increased breast cancer risk and is influenced by sex hormones. A T27C polymorphism (alleles A1 and A2, respectively) in the 5 promoter region of CYP17 may be associated with elevated sex hormone levels. In a cross-sectional study of 181 pre- and 173 postmenopausal women, we examined the relationship of this polymorphism with mammographic density and other risk factors for breast cancer. Subjects were recruited across five categories of density. Risk factor and dietary information, anthropometric measures, and blood samples were obtained. Sex hormone, lipid, growth factor levels, and CYP17 genotypes were determined. CYP17 genotype was not associated with mammographic density levels before or after adjusting for risk factors for breast cancer. In premenopausal women, the A2 allele was associated with higher levels of dehydroepiandrosterone sulfate, and in postmenopausal women, with higher levels of total estradiol and lower levels of follicle stimulating hormone. Among premenopausal women, interactions were observed between CYP17 genotype and endogenous insulin levels as well as dietary variables associated with mammographic density. Our findings suggest that the CYP17 A2 allele is associated with hormone levels, and interacts with insulin levels and diet to affect breast density levels and potentially breast cancer risk.     

Phenocopy breast cancer rates in Israeli <Emphasis Type="Italic">BRCA1</Emphasis><Emphasis Type="Italic">BRCA2</Emphasis> mutation carrier families: is the risk increased in non-carriers?

BRCA1 and BRCA2 mutation carriers have an increased risk for developing breast (and ovarian) cancer. Non-carriers from within such families (=true negatives) are counseled that their risk for developing breast cancer is similar to that of the average-risk population. Breast cancer diagnosed in a non-carrier from a family with a known mutation is coined phenocopy. The rate of breast cancer phenocopy and the risk for breast cancer in true negatives are unsettled. The rate of phenocopy breast cancer was assessed in non-carriers from Jewish families with a BRCA1 or BRCA2 mutation, identified at the Sheba medical center. Analysis was performed by t test for comparison of mean age at counseling or breast cancer diagnosis, and by calculating a standardized incidence ratio (SIR). Overall, 1318 females from 884 mutation carrying families (620 with BRCA1 264 with BRCA2 mutations) were genotyped, of whom 307 women from 245 families were assigned a true negative status (mean age at counseling 43.01 ± 13.03 years (range 19.7–92.8 years). Of these true negatives, 20 women (6.51–2.26% of families) developed breast cancer at a mean age of 54.1 ± 12.9 years (range 48.1 –60.1 years). The SIR for breast cancer in true negatives was not significantly different than the expected in the average-risk Israeli population [observed 20-expected 23.8 cases SIR = 0.84, 95% CI (0.51, 1.30)]. The rate of phenocopy breast cancer in non-carriers from Israeli BRCA1 BRCA2 mutation carrier families is 2.26% with no increased breast cancer risk over the average-risk population.     

Common <Emphasis Type="Italic">ERBB2</Emphasis> polymorphisms and risk of breast cancer in a white British population: a case–control study

Introduction  

About two-thirds of the excess familial risk associated with breast cancer is still unaccounted for and may be explained by multiple weakly predisposing alleles. A gene thought to be involved in low-level predisposition to the disease is ERBB2 (HER2). This gene is involved in cell division, differentiation, and apoptosis and is frequently amplified in breast tumours. Its amplification correlates with poor prognosis. Moreover, the coding polymorphism I655V has previously been associated with an increased risk of breast cancer.     

ΔNp73 regulates the expression of the multidrug-resistance genes <Emphasis Type="Italic">ABCB1</Emphasis> and <Emphasis Type="Italic">ABCB5</Emphasis> in breast cancer and melanoma cells - a short report

Purpose

Multidrug resistance (MDR) is a major cause of treatment failure. In cancer cells, MDR is often caused by an increased efflux of therapeutic drugs mediated by an up-regulation of ATP binding cassette (ABC) transporters. It has previously been shown that oncogenic ΔNp73 plays an important role in chemo-resistance. Here we aimed at unraveling the role of ΔNp73 in regulating multidrug resistance in breast cancer and melanoma cells.

Methods

KEGG pathway analysis was used to identify pathways enriched in breast cancer samples with a high ΔNp73 expression. We found that the ABC transporter pathway was most enriched. The expression of selected ABC transporters was analyzed using qRT-PCR upon siRNA/shRNA-mediated knockdown or exogenous overexpression of ΔNp73 in the breast cancer-derived cell lines MCF7 and MDA-MB-231, as well as in primary melanoma samples and in the melanoma-derived cell line SK-MEL-28. The ability to efflux doxorubicin and the concomitant effects on cell proliferation were assessed using flow cytometry and WST-1 assays.

Results

We found that high ΔNp73 levels correlate with a general up-regulation of ABC transporters in breast cancer samples. In addition, we found that exogenous expression of ΔNp73 led to an increase in the expression of ABCB1 and ABCB5 in the breast cancer-derived cell lines tested, while knocking down of ΔNp73 resulted in a reduction in ABCB1 and ABCB5 expression. In addition, we found that ΔNp73 reduction leads to an intracellular retention of doxorubicin in MDA-MB-231 and MCF7 cells and a concomitant decrease in cell proliferation. The effect of ΔNp73 on ABCB5 expression was further confirmed in metastases from melanoma patients and in the melanoma-derived cell line SK-MEL-28.

Conclusions

Our data support a role for ΔNp73 in the multidrug-resistance of breast cancer and melanoma cells.

     

A new <Emphasis Type="Italic">POT1</Emphasis> germline mutation—expanding the spectrum of <Emphasis Type="Italic">POT1</Emphasis>-associated cancers

Melanomas are associated with several hereditary conditions. We present a large family with several family members affected with primary melanomas and dysplastic nevi as well as thyroid cancer and other malignant tumors. Clinical work-up did not reveal a mutation in any of the genes usually considered with evaluation for predisposition to melanoma (BRCA1/2, CDKN2A, CDK4, PTEN, TP53). Whole exome sequencing of five affected family members showed a new variant in POT1. POT1 is associated with the telomere shelterin complex that regulates telomere protection and telomerase access. Germline mutations in POT1 were recently shown to be associated with hereditary predisposition to melanoma. Our findings support a role of POT1 germline mutations in cancer predisposition beyond melanoma development, suggesting a broader phenotype of the POT1-associated tumor predisposition syndrome that might also include thyroid cancer as well as possibly other malignant tumors.     

A tandem duplication of <Emphasis Type="Italic">BRCA1</Emphasis> exons 1–19 through <Emphasis Type="Italic">DHX8</Emphasis> exon 2 in four families with hereditary breast and ovarian cancer syndrome

Background

Physical activity is inversely associated with the risk of breast cancer among women in the general population. It is not clear whether or not physical activity is associated with the risk of BRCA-associated breast cancer.

Methods

We conducted a case–control study of 443 matched pairs of BRCA mutation carriers to evaluate the association between physical activity and breast cancer risk. Moderate and vigorous physical activities at ages 12–13, ages 14–17, ages 18–22, ages 23–29 and ages 30–34 were determined using the Nurses’ Health Study II Physical Activity Questionnaire. We estimated mean metabolic equivalent task hours/week for moderate, vigorous and total physical activities overall (ages 12–34), during adolescence (ages 12–17) and during early adulthood (ages 18–34). Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for total, moderate and strenuous recreational physical activities and breast cancer risk, by menopausal status.

Results

Overall, there was no significant association between total physical activity and subsequent breast cancer risk (OR_{Q4 vs. Q1} = 1.01, 95% CI 0.69–1.47; P-trend = 0.72). Moderate physical activity between ages 12–17 was associated with a 38% decreased risk of premenopausal breast cancer (OR_{Q4 vs. Q1} = 0.62; 95% CI 0.40–0.96; P-trend = 0.01). We found no association between exercise and breast cancer diagnosed after menopause.

Conclusions

These findings suggest that early-life physical activity is associated with a reduced risk of premenopausal breast cancer among BRCA mutation carriers.

Impact

Future prospective analyses, complemented by mechanistic evidence, are warranted in this high-risk population.

     

Detection of genetic instability at <Emphasis Type="Italic">HER-2/neu</Emphasis> and <Emphasis Type="Italic">p53</Emphasis> loci in breast cancer cells sing Comet–FISH

Summary A proportion of breast cancers acquire genetic alterations at 17q11.2–q12 (HER-2/neu), 20q13.2 (ZNF217 gene) and 17p13.1 (p53). We describe a unique technique (Comet–FISH) in which we documented relative genetic instability at p53 and HER-2/neu gene loci within a panel of malignant breast cancer cell lines (MCF-7; MDA-MB-468 and CRL-2336). Furthermore, Comet–FISH data were consistent with preferential repair of the p53 locus following gentoxic insult and suggest that this assay may be quite useful for the study of genetic instability.     

c-<Emphasis Type="Italic">myc</Emphasis>, not <Emphasis Type="Italic">her</Emphasis>-2/<Emphasis Type="Italic">neu</Emphasis>, can predict the prognosis of breast cancer patients: how novel,how accurate,and how significant?

The predictive and prognostic implication of oncogene amplification in breast cancer has received great attention in the past two decades. her-2/neu and c-myc are two oncogenes that are frequently amplified and overexpressed in breast carcinomas. Despite the extensive data on these oncogenes, their prognostic and predictive impact on breast cancer patients remains controversial. Schlotter and colleagues have recently suggested that c-myc, and not her-2/neu, could predict the recurrence and mortality of patients with node-negative breast carcinomas. Regardless of the promising results, caution should be exercised in the interpretation of data from studies assessing gene amplification without in situ analysis. We address the novelty, accuracy and clinical significance of the study by Schlotter and colleagues.     

Genetic polymorphisms of <Emphasis Type="Italic">XRCC1</Emphasis> (codon 399) and susceptibility to breast cancer in Iranian women,a case–control study

The X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair. In the present study, we specifically investigated whether common genetic variant in XRCC1 (exon 10, codon Arg399Gln) was associated with an altered risk of breast cancer. The eligible cases were patients at chemotherapy unit of Nemazi hospital, Shiraz Iran, from October 1999 to August 2000 and from July 2004 to July 2005. The present study included 186 females with breast cancer. Age frequency-matched controls were randomly selected from the healthy females blood donor, according to the age distribution of the cases. A total of 187 healthy females included in the study. Using PCR-based method, the XRCC1 Arg399Gln polymorphism was determined. In control group the 399Gln allele frequency was 32.6%. The genotypic frequencies of the control subjects did not show significant deviation from Hardy-Weinberg equilibrium (χ² = 1.683, df = 1, P > 0.05). A statistically significant association was observed in comparison between Gln/Gln and Arg/Arg genotype (OR = 2.01, 95% CI:1.02–3.94, P = 0.041). There was no linear trend for presence of 0, 1, and 2 of the 399Gln allele and risk of breast cancer (χ² = 1.212, P = 0.271). In the recessive effect of the Gln allele (comparison between Gln/Gln vs. Arg/Arg+Arg/Gln), Gln/Gln genotype significantly increased the risk of breast cancer (OR = 2.31, 95% CI:1.21–4.35, P = 0.010). In the dominant effect of the Gln allele (comparison between Gln/Gln+Arg/Gln vs. Arg/Arg), Gln/Gln+Arg/Gln genotypes was not associated with the risk of breast cancer (OR = 0.95, 95% CI:0.63–1.42, P = 0.799). It is concluded that 399Gln allele may act as a recessive allele and increase the breast cancer risk. This study was supported by Shiraz University.     

Glucosylceramide synthase upregulates <Emphasis Type="Italic">MDR1</Emphasis> expression in the regulation of cancer drug resistance through <Emphasis Type="Italic">cSrc</Emphasis> and β-catenin signaling

Background  

Drug resistance is the outcome of multiple-gene interactions in cancer cells under stress of anticancer agents. MDR1 overexpression is most commonly detected in drug-resistant cancers and accompanied with other gene alterations including enhanced glucosylceramide synthase (GCS). MDR1 encodes for P-glycoprotein that extrudes anticancer drugs. Polymorphisms of MDR1 disrupt the effects of P-glycoprotein antagonists and limit the success of drug resistance reversal in clinical trials. GCS converts ceramide to glucosylceramide, reducing the impact of ceramide-induced apoptosis and increasing glycosphingolipid (GSL) synthesis. Understanding the molecular mechanisms underlying MDR1 overexpression and how it interacts with GCS may find effective approaches to reverse drug resistance.     

Genetic polymorphisms of 3′-untranslated region of <Emphasis Type="Italic">SULT1A1</Emphasis> and their impact on tamoxifen metabolism and efficacy

Purpose

Despite the recent expansion in the use of immunotherapy for many cancer types, it is still not a standard treatment for breast cancer. Identifying differences in the immune systems of breast cancer patients compared to healthy women might provide insight into potential targets for immunotherapy and thus may assist its clinical implementation.

Methods

Multi-colour flow cytometry was used to investigate myeloid and lymphoid populations in the peripheral blood of breast cancer patients (n = 40) and in the blood of healthy age-matched women (n = 25). We additionally performed functional testing to identify immune suppressive mechanisms used by circulating CD14+ myeloid cells from breast cancer patients.

Results

Our results show that breast cancer patients have significantly elevated frequencies of cells with the monocytic myeloid-derived suppressor cell (mMDSC) phenotype CD14+ HLA-DR?/low compared with healthy women (p < 0.01). We also observed higher levels of earlier differentiated T cells and correspondingly lower levels of T cells in later stages of differentiation (p < 0.05). These disease-associated differences could already be detected in early-stage breast cancer patients in stages 1 and 2 (n = 33 of 40) (p < 0.05). Levels of circulating T cells correlated with certain clinical features and with patient age (p < 0.05). Functional tests showed that CD14+ myeloid cells from breast cancer patients more potently suppressed autologous T cell proliferation than CD14+ cells from healthy women (p < 0.01). Subsequent investigation determined that suppression was mediated in part by reactive oxygen species, because inhibiting this pathway partially restored T cell proliferation (p < 0.01).

Conclusion

Our results highlight the potential importance of cells with mMDSC phenotypes in breast cancer, identifiable already at early stages of disease. This may provide a basis for identifying possible new therapeutic targets to enhance anti-cancer immunity.