Immediate surgical mesh-free implant-based breast reconstruction with fascial flap in breast cancer patients after mastectomy.

PURPOSE: Surgical meshes are often used in retro-pectoral implant-based breast reconstruction (IBBR) to improve lower pole expansion. However, using of surgical meshes is associated with increased complications and costs. To solve this problem, we have adopted a modified fascia-based IBBR technique using fasciae of pectoral major, serratus anterior, and external oblique muscles to form a sling covering the lower pole of prosthesis since 2014. METHODS: Data of 788 retro-pectoral IBBR cases, including 250 fascia-based IBBR cases (fascial group) and 538 traditional IBBR cases (control group), treated between 2014 and 2019 were retrospectively analyzed. The surgical outcomes of the fascial and control group were compared. The primary endpoint was the rate of post-operative complications requiring interventions. The secondary endpoint was the rate of explantation. The exploratory endpoint was the time from surgery to complication and explantation. RESULTS: The fascial group had significantly lower rates of developing major post-operative complications (1.2 vs. 6.1%, p = 0.002) and losing prostheses (1.2 vs. 4.3%, p = 0.025), as compared with the control group. The median time from surgery to complication and explantation were 61 (range, 35-115) days and 92 (range, 77-134) days for the fascial group and 35 (range, 6-239) days and 63 (range, 23-483) days for the control group, respectively. CONCLUSION: Fascia-based IBBR technique had low rates of major post-operative complications and explantation. Fascia-based IBBR technique could be considered as an alternative reconstruction method in properly selected patients.

Immediate Prosthesis Breast Reconstruction: A Comparison Between Ambulatory Surgery Versus Traditional Hospitalization Based on the Propensity Score Matching Method.

BACKGROUND: The positive benefits of immediate prosthesis breast reconstruction (IPBR) are incontrovertible. During the COVID-19 pandemic, health care resources became scarce. The implementation of outpatient immediate prosthesis breast reconstruction (OIPBR) can improve the efficiency of medical care and reduce viral exposure. Very few studies have focused on OIPBR and this study aimed to fill this gap by evaluating outcomes of OIPBR compared with traditional hospitalization IPBR (THIPBR) in terms of complications and quality of life. MATERIAL AND METHODS: The study enrolled patients undergoing IPBR at Tianjin Medical University Cancer Institute and Hospital between January 1, 2020, and September 30, 2021. Outcomes were defined as postoperative complications and quality of life before reconstruction and at 3-month follow-up. Quality of life was assessed by BREAST-Q questionnaire. Inverse probability of treatment weighting and propensity score matching (PSM) were applied to adjust for confounders. RESULTS: A total of 135 patients were enrolled, including 110 with THIPBR and 25 with OIPBR. After matching, baseline characteristics were well balanced. Patients with OIPBR had lower rates of lymphedema on the surgery side (p = 0.041) and readmission (p = 0.040) than patients with THIPBR. No statistically significant differences in the quality of life metrics of psychosocial well-being, sexual well-being, satisfaction with breast and physical well-being of the chest were found between the two groups. CONCLUSION: OIPBR is a safe and efficient alternative to THIBPR during the COVID-19 pandemic. It is recommended when medical conditions allow to conserve medical resources. Accelerated technical training for the performance of OIPBR at the hospital level should be expedited. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

miR-485-5p suppresses breast cancer progression and chemosensitivity by targeting survivin.

Breast cancer is the most common cancer among women worldwide. Chemoresistance remains to be a considerable obstacle in breast cancer therapy and it is often involves dysregulation of a variety of microRNAs (miRNAs). miR-485-5p functions as a tumor suppressor in several types of human cancers. However, its role in breast cancer chemosensitivity have not been determined. In the present study, we demonstrated that overexpression of miR-485-5p suppresses breast cancer progression and enhances chemosensitivity both in vitro and in vivo. Further study demonstrated that miR-485-5p directly targeted the 3'-untranslated region of survivin and overexpression of survivin overcomes the miR-485-5p induced effects on breast cancer. In conclusion, our study identified that miR-485-5p suppresses cancer progression and enhances the chemosensitivity by targeting survivin. Targeting survivin by miR-485-5p may provide a potential approach to reverse chemosensitivity in breast cancer cells.

FoxD3 deficiency promotes breast cancer progression by induction of epithelial-mesenchymal transition.

The transcription factor forkhead box D3 (FOXD3) plays an important role in the development of neural crest and gastric cancer cells. However, the function and mechanisms of FOXD3 in the breast tumorigenesis and progression is still limited. Here, we report that FOXD3 is a tumor suppressor of breast cancer tumorigenicity and aggressiveness. We found that FOXD3 is down-regulated in breast cancer tissues. Patients with low FOXD3 expression have a poor outcome. Depletion of FOXD3 expression promotes breast cancer cell proliferation and invasion in vitro, whereas overexpression of FOXD3 inhibits breast cancer cell proliferation and invasion both in vitro and in vivo. In addition, depletion of FOXD3 is linked to epithelial-mesenchymal transition (EMT)-like phenotype. Our results indicate FOXD3 exhibits tumor suppressive activity and may be useful for breast therapy.

Germline genetic variants disturbing the Let-7/LIN28 double-negative feedback loop alter breast cancer susceptibility.

Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7-induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0 × 10⁻5. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk.

Preservation of the pectoralis major fascia has no impact on the long-term oncologic outcomes of patients with breast cancer treated with conservative mastectomy and immediate breast reconstruction: A propensity score matching analysis.

BACKGROUND: The oncologic safety of preserving the pectoralis major fascia (PMF) in patients with breast cancer remains controversial. In this study, we aimed to determine the impact of preserving the PMF on long-term oncologic outcomes in patients with breast cancer treated with immediate implant-based breast reconstruction (IBBR) following conservative mastectomy. METHODS: We selected women with early-stage breast cancer who underwent conservative mastectomy and submuscular IBBR in our center during 2014-2019. The propensity score matching method was used to create well-balanced fascia-preserved and fascia-removed groups. Locoregional recurrence-free survival (LRFS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared using log-rank tests between the fascia-preserved and fascia-removed groups. RESULTS: After matching, there were 219 patients in each group. The mean follow-up time was 64.8 ± 18.1 months for the fascia-preserved group and 64.9 ± 18.4 months for the fascia-removed group. There were no significant differences between the groups in terms of LRFS (91.3% vs. 93.8%; p = 0.818), DMFS (94.0% vs. 92.3%; p = 0.056), DFS (89.9% vs. 88.4%; p = 0.261), and OS (95.8% vs. 95.4%; p = 0.783) rates. In the fascia-preserved group, 61.5% of the locoregional recurrence events occurred within 2 years after surgery. CONCLUSION: Preservation of the PMF did not significantly impact the long-term oncologic outcomes in patients with breast cancer who underwent conservative mastectomy and IBBR. The PMF might be safely preserved in patients without suspicious tumor invasion into this fascia.

The associations between two polymorphisms in the interleukin-10 gene promoter and breast cancer risk.

The association between single-nucleotide polymorphisms (SNPs) in the interleukin-10 (IL-10) gene promoter and breast cancer risk is still ambiguous. We here performed a meta-analysis based on the evidence currently available from the literature to make a more precise estimation of the relationship between two genetic variants in the IL-10 gene promoter, -1082A > G (rs1800896) and -592C > A (rs1800872), and breast cancer. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the corresponding strengths of association under the codominant, dominant, and recessive models. A total of ten studies (4,181 cases and 4,384 controls) were eligible for meta-analysis. There were six studies with 3,032 cases and 3,190 controls for rs1800872, and eight studies with 1,636 cases and 1,670 controls for rs1800896. Meta-analysis showed that neither of the two polymorphisms had any association with increased breast cancer risk (for rs1800896: OR = 1.060, 95% CI = 0.785-1.432 in the dominant model, and OR = 1.152, 95% CI = 0.958-1.386 in the recessive model; and for rs1800872: OR = 0.952, 95% CI = 0.859-1.056 in the dominant model, and OR = 0.892, 95% CI = 0.741-1.072 in the recessive model). The results did not change when the analyses were restricted in Caucasians, or in the studies fulfilling Hardy-Weinberg equilibrium, or according to source of controls. In outlier analysis, no individual study affected the overall OR dominantly, since omission of any single study made no material huge difference. In conclusion, the present meta-analysis suggests a lack of association between the two SNPs (rs1800896 and rs1800872) in the IL-10 gene promoter and breast cancer risk. Further studies, either with larger sample size or regarding other SNPs/haplotypes within the IL-10 gene, are needed to clarify the role of IL-10 in breast carcinogenesis.

The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer.

Increasing evidence has shown that chemokines and chemokine receptors are associated with tumor growth and metastasis. CCR4, an important chemokine receptor for regulating immune homeostasis, is thought to be involved in hematologic malignancies and has also recently implicated in some solid tumors, such as gastric cancer. The possible role of CCR4 in breast cancer has not been well elucidated. In this study, we show that CCR4 is differentially expressed in human breast cancer cell lines. Specifically, we find that CCR4 is overexpressed in breast cancer cell lines with high metastatic potential. More importantly, we used a combination of overexpression and RNA interference to demonstrate that CCR4 promotes breast tumor growth and lung metastasis in mice. Furthermore, we find that microvessel density is significantly increased in tumors formed by CCR4-overexpressing cells and decreased in those formed by CCR4-knockdown cells. We find that overexpression of CCR4 can enhance the chemotactic response of breast cancer cells to CCL17. However, the expression of CCR4 does not affect the proliferation of breast cancer cells in vitro. Furthermore, we show that CCR4 expression is positively correlated with HER2 expression, tumor recurrence and lymph node, lung and bone metastasis (P < 0.05). Multivariate analysis showed that CCR4 expression is a significant independent prognostic factor for overall survival (P = 0.036) but not for disease-free survival in patients with breast cancer (P = 0.071). Survival analysis indicated a strong association between CCR4 expression and lower overall survival (P = 0.0001) and disease-free survival (P = 0.016) in breast cancer.

Triple-Negative Breast Cancer with Dermatomyositis: A Case Report and Literature Review.

PURPOSE: Dermatomyositis (DM) is an autoimmune inflammatory myopathy, the onset of which is sometimes associated with some malignancies and sometimes appears as a symptom of paraneoplastic syndrome. The main symptoms include progressive proximal muscle weakness, extra muscular manifestations such as dyspnea or dysphagia, and skin changes. There is currently no standardized treatment for breast cancer associated with DM. PATIENTS AND METHODS: We report a 45-year-old woman with a palpable mass over the left external breast along with diffuse erythema on the shoulder, orbital edema, voice hoarseness, dyspnea, and weakness of the extremities. Needle aspiration biopsy and imaging suggested malignancy. Thus, breast-conserving surgery and pectoral myotomy biopsy+ skin excision biopsy were performed. Pathology confirmed triple-negative breast cancer (TNBC) and DM. Two days after surgery, the patient's orbital edema, voice hoarseness, dyspnea, and weakness of the extremities were significantly reduced, and the erythema subsided significantly. Left axillary lymph node dissection was performed after postoperative adjuvant chemotherapy, and the nodes were negative. The patient was recovering well, and follow-up showed no signs of recurrence or metastasis. CONCLUSION: Be alert for the presence of malignancy when a breast cancer patient presents with DM, a test for dermatologists, rheumatologists, and oncologists. This case demonstrated the effectiveness of breast-conserving surgery combined with radiotherapy for early-stage triple-negative breast cancer with DM, even without further treatment for DM to reduce the symptoms. In conclusion, the treatment plan for these patients depends on the presentation of the tumor and DM.

The clinical efficacy and safety of acupuncture intervention on cancer-related insomnia: A systematic review and meta-analysis.

Objective: To evaluate the efficacy and safety of acupuncture in treating symptoms for Cancer-related Insomnia(CRI) patients. Methods: Seven databases were searched from the time of database establishment to 31 March 2022. Randomized Controlled Trials (RCTs) on acupuncture intervention for CRI were collected. Literature screening and data extraction were performed independently by two researchers. Meta-analysis was performed using RevMan 5.4 software. Results: A total of 13 articles with 1,109 participants were included. Five hundred and seventeen in the treatment group and 592 in the control group. Ten of the RCTs used the PSQI rating scale and four randomized controlled trials used the ISI rating scale, and the PSQI and ISI were analyzed together as continuous data. The results of the meta-analysis were: MD = -1.83, 95%CI = [-2.71, -0.94], P < 0.0001, indicating a significant improvement in PSQI scores in patients with CRI by acupuncture intervention; MD = 0.79, 95%CI = [-0.46, 2.03], P = 0.22. Acupuncture was not statistically significant on ISI scores for patients with CRI compared to controls, which does not yet indicate that acupuncture is effective for symptoms in patients with CRI. The results of the meta-analysis of the other 4 items using sleep disorder logs as efficacy analysis data were as follow, relative risk RR = 0.47, 95%CI = [0.33, 0.66], P < 0.0001. The difference was statistically significant, indicating that acupuncture can improve the symptoms of CRI patients compared to control group. Conclusion: Acupuncture can improve the symptoms of patients with CRI to some extent, but due to the relatively small number and low quality of the included literature in this study, more high-quality clinical trials are needed as supplement the evidences in future. Systematic review registration: https://www.crd.york.ac.uk/prospero/.

RAD51 135G>C does not modify breast cancer risk in non-BRCA1/2 mutation carriers: evidence from a meta-analysis of 12 studies.

A single-nucleotide polymorphism (SNP) in the 5'-untranslated region (UTR) of RAD51, 135G>C (rs1801320), was reported to be associated with an increased risk of breast cancer among BRCA2 as well as BRCA1 carriers. A few studies have also investigated the genetic contribution of RAD51 135G>C to the risk of sporadic breast cancers or breast cancer in non-BRCA1/2 carriers, though the results are yet controversial and inconclusive. We, in this study, performed a more precise estimation of the relationship between 135G>C and breast cancer among non-BRCA1/2 mutation carriers by meta-analyzing the currently available evidence from the literature. A total of 12 studies involving 7,065 cases and 6,981 controls were identified. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. When all the studies were pooled into the meta-analysis, there was no evidence for a significant association between 135G>C and breast cancer risk in non-BRCA1/2 mutation carriers (for CC vs. GG: OR = 0.995, 95%CI: 0.741-1.336; for GC vs. GG: OR = 0.959, 95%CI: 0.869-1.057; for dominant model: OR = 0.988, 95%CI: 0.902-1.082; and for recessive model: OR = 1.037, 95%CI: 0.782-1.376). We also performed subgroup analysis by ethnicity (Caucasian) as well as did analysis using the studies fulfilling Hardy-Weinberg equilibrium, and the results did not change. In summary, the present meta-analysis suggests that the RAD51 135G>C does not modify breast cancer risk in non-BRCA1/2 mutation carriers.

A systematic review of the relationship between polymorphic sites in the estrogen receptor-beta (ESR2) gene and breast cancer risk.

The estrogen signal is mediated by the estrogen receptor (ER). The specific role of ER-beta, a second ER, in breast carcinogenesis is not known. A number of association studies have been carried out to investigate the relationship between polymorphic sites in the ESR2 gene and breast cancer risk, however, the results are inconsistent. We searched PubMed, Medline, and Web of Science database (updated to 10 January 2010) and identified 13 relevant case-control studies, and approximately 28 single-nucleotide polymorphisms (SNPs) and one micro-satellite marker were reported in the literature. The median number of study subjects was 776 (range 158-13,550). Three genetic variants [(CA)n, rs2987983, and rs4986938] showed significant overall associations with breast cancer, and rs4986938 was reported twice. Because rs4986938 and rs1256049 were the most extensively studied polymorphisms, we subsequently conducted a meta-analysis to evaluate their relationship with breast cancer risk (9 studies of 10,837 cases and 16,021 controls for rs4986938; 8 studies of 11,652 cases and 15,726 controls for rs1256049). For rs4986938, the women harboring variant allele seemed to be associated with a decreased risk either in the dominant model [pooled OR = 0.944, 95% confidence interval (95% CI) 0.897-0.993, fixed-effects] or in the co-dominant model (AG vs. GG) (OR = 0.944, 95% CI 0.895-0.997, fixed-effects). rs1256049 was not associated with breast cancer risk in any model. Five studies had investigated the effect of haplotypes in the ESR2 gene on breast cancer risk, and four of them had positive outcomes. In summary, the present systematic review suggests that SNP rs4986938 as well as haplotypes in the ESR2 gene might be associated with breast cancer. The need for additional studies examining these issues seems of vital importance.

No association between a progesterone receptor gene promoter polymorphism (+331G>A) and breast cancer risk in Caucasian women: evidence from a literature-based meta-analysis.

Sex steroid hormones and their receptors such as estrogen receptor (ER) and progesterone receptor (PgR) have been widely studied for their roles in the etiology of breast cancer. To date, many studies have evaluated the association between a functional polymorphism in the PgR gene promoter (+331G>A, rs10895068) and breast cancer risk; however, the result is still ambiguous and inconclusive. In order to derive a more precise estimation of the association, a meta-analysis was performed in this study. By searching relevant literature, a total of 10 studies containing 13,702 cases and 14,726 controls (28,428 subjects in total) were identified and meta-analyzed. All the study subjects were Caucasian women. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the codominant model, dominant model, and recessive model. Overall, no significant association between +331G>A polymorphism and breast cancer susceptibility was observed for AA versus GG (OR = 0.940, 95% CI: 0.566-1.562), GA versus GG (OR = 1.061, 95% CI: 0.888-1.267), AA + GA versus GG (OR = 1.074, 95% CI: 0.956-1.207), and AA versus GA + GG (OR = 0.951, 95% CI: 0.586-1.544). Sensitivity analysis was performed by limiting the meta-analysis to those studies fulfilling Hardy-Weinberg equilibrium, and the results were not materially altered in any genetic model. In conclusion, the present meta-analysis strongly suggests that +331G>A in the PgR gene is not associated with breast cancer risk.

Current evidence on the relationship between polymorphisms in the COX-2 gene and breast cancer risk: a meta-analysis.

The association between single-nucleotide polymorphisms (SNPs) in the COX-2 gene and breast cancer risk is still ambiguous. We here try to derive a more precise estimation of the relationship by performing a meta-analysis based on currently available evidence from literature. More than 15 SNPs have been studied, and the most studied genetic variants were rs5275, rs5277, and rs20417. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association between each polymorphism and breast cancer risk under the codominant model, dominant model, and recessive model, respectively (nine studies with 6,968 cases and 9,126 controls for rs5275; three studies with 2,901 cases and 3,463 controls for rs20417; two studies with 5,551 cases and 6,208 controls for rs5277). No overall significant associations were observed in single-locus analysis between the three polymorphisms of COX-2 and breast cancer risk, though a borderline significant increased risk of breast cancer was detected with rs5277 in a recessive model (OR: 1.217, 95% CI: 0.958-1.547, P = 0.107). The results were not changed when studies were stratified by ethnicity. In conclusion, the present meta-analysis suggests that none of the most studied three SNPs (rs5275, rs20417, and rs5277) in the COX-2 gene is a conspicuous low-penetrant risk factor for developing breast cancer. There is a need for further large studies into the role of these polymorphisms (especially rs5277) and other potentially functional polymorphisms/haplotypes in the COX-2 gene as breast cancer risk modifiers.

Lack of an association between a functional polymorphism in the interleukin-6 gene promoter and breast cancer risk: a meta-analysis involving 25,703 subjects.

The association between a single-nucleotide polymorphism (SNP) -174G > C (rs1800795) located in the IL-6 gene promoter and breast cancer risk is still controversial and ambiguous. We performed in this study a more precise estimation of the relationship by meta-analyzing the currently available evidence from literature. A total of 11 publications containing 12 studies including 10,137 cases and 15,566 controls were identified. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the codominant model, dominant model, and recessive model. When all the studies were pooled into the meta-analysis, there was no evidence showing a significant association between -174G > C and breast cancer risk (for CC vs. GG: OR = 1.024, 95% CI: 0.935-1.121; for GC vs. GG: OR = 1.008, 95% CI: 0.946-1.073; for dominant model: OR = 0.980, 95% CI: 0.857-1.121; and for recessive model: OR = 1.027, 95% CI: 0.944-1.117). In the subgroup analyses by ethnicity, no significant associations were observed in any genetic models. In summary, the present meta-analysis suggests that the functional polymorphism -174G > C within the IL-6 gene promoter is not associated with breast cancer risk. Identifying a unique SNP as a breast cancer risk predictor remains a very challenging task.

XRCC2 Arg188His polymorphism is not directly associated with breast cancer risk: evidence from 37,369 subjects.

Several common single-nucleotide polymorphisms (SNPs) within the XRCC2 gene have been identified as potential breast cancer susceptibility loci and a coding SNP in exon 3 (Arg188His, rs3218536) has been extensively studied, though the results were inconclusive. We, in this study, performed a more convincing and precise estimation of the relationship between Arg188His and breast cancer by meta-analyzing the currently available evidence from literature. A total of 16 studies involving 18,341 cases and 19,028 controls (37,369 subjects) were identified for meta-analysis. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the codominant model, dominant model, and recessive model. When all the studies were pooled into meta-analysis, there was no evidence of a significant association between Arg188His and breast cancer risk in any genetic models. Notably, Arg188His tended to be related to breast cancer in a fixed-effects, dominant model (OR = 0.922, 95% CI: 0.870-0.978, P = 0.007); however, since there was a between-study heterogeneity (P (h) = 0.014), we assessed the association using a random-effects model instead and no significance was observed (OR = 0.932, 95% CI: 0.852-1.020, P = 0.128). Subgroup analysis by ethnicity did not change the results. In summary, the present meta-analysis suggests that the XRCC2 Arg188His is not directly associated with breast cancer risk. However, considering that susceptibility is likely to be the result of a complex interplay between genetic variation and environmental factors, we cannot rule out the possibility of interactions between Arg188His and other variants. Further investigation on the influence of this SNP in modifying the relationship between environment exposures and breast cancer risk is still needed.

Genetic variants in GSTM3 gene within GSTM4-GSTM2-GSTM1-GSTM5-GSTM3 cluster influence breast cancer susceptibility depending on GSTM1.

Mu class of Glutathione-S-transferase (GSTM) genes arrange in a tandem on chromosome 1p13.3. The relationship between genetic variants in the GSTM1-5 gene cluster and breast cancer is still ambiguous. In the present study, 17 tagging single-nucleotide polymorphisms (SNPs) covering the GSTMs cluster were originally selected and 11 validated SNPs were used for genotyping 921 cases and 711 controls. The association analyses were performed according to the absence or presence of GSTM1. In the GSTM1-/- group, the allele frequency of one SNP in GSTM3 was significantly different between cases and controls (P = 2.0 x 10(-4), corrected P = 0.001), with odds ratio of 1.75 (95% confidence interval, 1.26-2.44). The observed association in the GSTM1-/- group was successfully replicated in an independent population set (familial/early-onset breast cancer cases, n = 267; community-based controls, n = 667). The combined P values were robust (10(-6)) and the false positive report probability (FPRP) values were low. In contrast, no susceptibility allele/haplotype was identified when the GSTM1 gene was present. Based on epidemiological observations, we further identified two genetic variants in the GSTM3 locus accounting for differential expression of GSTM3 in normal breast tissues by such means as altering binding of RNA-pol-II. Protective genotypes were correlated with higher GSTM3 expression levels. In conclusion, SNPs/haplotypes in the GSTM3 gene within the GSTMs gene cluster are likely to contribute to breast cancer risk when the GSTM1 is absent. We infer that GSTM3 catalyzing ability in normal breast tissue might protect against breast carcinogenesis.

Toll-like receptor 3 -926T>A increased the risk of breast cancer through decreased transcriptional activity.

Toll-like receptor 3 (TLR3) is a viral sensor that induces apoptosis in response to double-stranded RNA (dsRNA). Common genetic changes in the TLR3 gene may influence breast cancer susceptibility and development. However, all of the polymorphisms in the previous study were only markers of the TLR3 gene, not causative polymorphisms. In this study, we performed a case-control study focusing on the relationship between rs5743305 (-926T>A), a single nucleotide polymorphism (SNP) in the promoter region of TLR3, and breast cancer. We found that the genetic variant rs5743305 increased the risk of breast cancer under the dominant and codominant models (dominant model: AT+AA vs TT.: OR = 1.3023, 95%CI: 1.0778-1.5736, P = .0062; codominant model: AA vs. TT: OR = 1.3919, 95%CI: 1.0177-1.9036, P = .0384; AT vs. TT: OR = 1.2799, 95%CI: 1.0475-1.5639, P = .0158) but not under the recessive model (TT vs. AT+AA, OR = 1.2387, 95%CI: 0.9197-1.6682, P = .1588). The same trends were found in the age-adjusted logistic regression study and stage 2 study. Furthermore, the electrophoretic mobility shift assay (EMSA) and luciferase reporter assay showed that rs5743305 decreased the transcriptional activity of TLR3. There was consistently reduced TLR3 mRNA and protein expression in human breast cancer samples from patients with TLR3 - 926A. Therefore, TLR3 rs5743305 increases the risk of breast cancer by decreasing the transcriptional activity of TLR3. This study may provide a better understanding of the genetic architecture underlying disease susceptibility and may advance the potential for preclinical prediction in future genetic testing.

Toll-like receptor 3 acts as a suppressor gene in breast cancer initiation and progression: a two-stage association study and functional investigation.

Toll-like receptor 3 (TLR3) is a receptor recognizing double-stranded RNA (dsRNA) from viruses as well as from lytic mammalian cells. In the present study, we performed a two-stage association study (n = 3,551) and found that the minor alleles of two SNPs (the T-allele of rs5743312 and the T-allele of rs3775296) conferred increased risks of breast cancer incidence. The adjusted odds ratios (ORs) were 2.281 (P = 7.01 × 10-5) and 2.086 (P = 8.69 × 10-5), respectively. Specifically, the susceptibility variants within TLR3 were significantly associated with larger tumor size (adjusted P-values: 0.004 for rs5743312 and 0.004 for rs3775296). Furthermore, we investigated the biological function of the TLR3 protein in breast cancer cell lines. Notably, the stable expression of TLR3 directly inhibited cell proliferation both in vitro and in vivo. We also verified that TLR3 conferred less invasive phenotypes on breast cancer cells by regulating the mRNA expression of a panel of genes. TLR3-mediated inhibition of proliferation was caused by downregulation of the EGFR/PI3K/AKT pathway. In summary, our findings strongly suggest that common genetic changes in the TLR3 gene may influence breast cancer susceptibility and development, and TLR3 plays a negative regulatory role in the initiation and progression of human breast cancer cells, at least in part by downregulating the EGFR/PI3K/AKT pathway.

Estrogen receptor-α-miR-1271-SNAI2 feedback loop regulates transforming growth factor-ß-induced breast cancer progression.

BACKGROUND: Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. ERα has been identified to promote the growth of primary breast cancer, however, it can also antagonize signaling pathways that lead to epithelial-mesenchymal transition (EMT), including transforming growth factor-ß (TGF-ß) signaling. miRNA alteration or dysfunction is involved in cancer development and progression. Although miR-1271 has identified as a tumor suppressor in various cancers, the role of miR-1271 in breast cancer is still limited. METHODS: The effect of miR-1271 on breast cancer progression was investigated both in vitro and in vivo. The EMT-related protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of ERα-miR-1271-SNAI2 feedback loop. RESULTS: miR-1271 suppresses breast cancer progression and EMT phenotype both in vitro and in vivo by targeting SNAI2. Estrogen reverses TGF-ß-induced EMT in a miR-1271 dependent manner. Furthermore, ERα transactivates the miR-1271 expression and is also transcriptionally repressed by SNAI2. CONCLUSIONS: Our data uncover the ERα-miR-1271-SNAI2 feedback loop and provide a mechanism to explain the TGF-ß network in breast cancer progression.