Response to trastuzumab and investigation of expression profiles of matrix metalloproteinase-related proteins in primary breast cancer stem cells

Clinical and Experimental Medicine - Breast cancer (BC) is the leading cause of cancer deaths in women. One of the reasons for the failure of BC treatment is reportedly the ineffectiveness of...     

Contribution of BRCA1 and BRCA2 germ-line mutations to the incidence of breast cancer in young women: results from a prospective population-based study in France

The prevalence of BRCA1/2 germ-line mutations was assessed in a prospective population-based series of early-onset breast cancer (BC) patients in France, and the usefulness of a clinical assessment of hereditary BC risk, based on multiple criteria including pedigree structure, was evaluated. Through the Rhone region BC registry, 232 women diagnosed with BC before 46 years of age were included. They were tested for BRCA1/2 mutations an average of 10 months after diagnosis. All the women were classified according to their family history of cancer: high risk of hereditary breast cancer (HBC), low risk of HBC, isolated BC, and unknown HBC risk. Deleterious mutations were observed in 21 women (9.1%): 15 (6.5%) BRCA1 and 6 (2.6%) BRCA2. Mutations were more prevalent in women who developed BC before age 41 than in women who developed BC between ages 41 and 45 (12.8% versus 5.2%, respectively, P = 0.04). A high prevalence of BRCA1/2 mutations was found among women in the high-risk category with particular family features (i.e., small family size, predominantly male pedigree, specific cancers; 23.5%) and among women with isolated BC before age 41 and with five or fewer close adult female relatives (16.6%). According to the 10% probability level recommended by the American Society of Clinical Oncology guidelines for genetic testing of cancer, BRCA1/2 mutation screening should be considered for all women diagnosed before age 41, except for those with isolated BC in a large pedigree including multiple unaffected female relatives. The clinical assessment of HBC risk that we have developed should help in the decision to perform genetic testing.     

Clinical,pathological and genetic features of women at high familial risk of breast cancer undergoing prophylactic mastectomy

Prophylactic mastectomy (PM) is a risk-management option for women at high familial risk of breast cancer (BC). This study describes the PM experience of women enrolled in a large observational cohort study involving families with a history of hereditary breast cancer. Within 357 multiple-case BC families [119 (33%) BRCA1 or BRCA2 mutation positive], identified via family cancer clinics, 49 cases of PM [21 (43%) BRCA1 or BRCA2 mutation positive] were identified and their clinical, pathological and genetic features reviewed. Families with at least one incidence of PM displayed stronger breast/ovarian cancer histories than did families without PM. Median age at time of PM was 45 years (range 28-58). Ten cases (21%) were bilateral PMs in unaffected women and 39 cases were contralateral PMs in women with prior invasive BC (71%) or ductal carcinoma in situ (DCIS) (8%). Most (88%) underwent total mastectomy. Unnecessary axillary surgery occurred in eight subjects (16%). Malignant histology was found in three PM specimens (6%). Prior to genetic testing, PM was performed in two women who were subsequently shown not to carry the mutation specific to their family. Optimal utilization of genetic testing to guide surgical decision making, appropriate surgical technique and careful pathology examination of PM specimens, are important issues to consider prior to PM in women at high familial risk of BC.     

Insulin resistance, obesity and breast cancer risk

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

Worldwide review with meta-analysis of women’s awareness about breast cancer

ObjectiveTo summarize the awareness levels of breast cancer (BC) worldwide and investigate factors associated with BC awareness to determine differences in awareness between China and other countries.MethodsThis systematic review followed the PRISMA guidelines and included 92 articles up to July, 2021. We calculated percentages for BC awareness levels and conducted subgroup analysis and cumulative meta-analysis.ResultsA total 84% (95% confidence interval [95%CI]: 78–90%) of women knew about BC; however, only 51% (95%CI: 37–66%) and 40% (95%CI: 24–56%) of women were aware of BC symptoms and BC risk factors, respectively. The most commonly known BC symptom was breast lump (71%, 95%CI: 62–80%), and BC family history was the most well-known BC risk factor (61%, 95%CI: 54–69%). Subgroup analysis showed lower awareness levels among Chinese and Asian women than women from other countries. Cumulative meta-analysis showed no obvious progress in BC awareness levels over time. We investigated 15 awareness-related factors, the most frequent of which were education level (61.8%), occupation (29.4%), and age (26.5%).ConclusionBC awareness levels remain low. Improving BC awareness is critical, especially in developing countries.Practice ImplicationsEffective education programs are urgently needed to improve women’s BC awareness.     

Axillary lymph node morphology in women with in situ breast carcinoma

Summary Axillary lymph nodes in 184 female autopsy cases were studied using morphological criteria. Special attention was paid to the morphology in 34 women with in situ breast carcinoma (in situ BC) compared to the remaining women without malignant breast lesions, who served as controls. Sinus histiocytosis (SH) and diffuse cortical hyperplasia (DCH) were significantly more frequent among women with in situ BC compared to controls. No significant association was found between unilateral in situ BC and these lymph node patterns on the contralateral side. Germinal center and follicular hyperplasia (GCH/FH), lymphocyte depletion (LD), fibrosis, hyalinization, calcifications and lipomatosis were not associated with in situ BC. The results indicate that in situ BC provokes reactive morphological changes of the regional axillary lymph nodes similar to the changes associated with a good prognosis in women with invasive breast cancer (IBC).     

Psychological and social determinants of women's decisions to undergo genetic counseling and testing for breast cancer

This study examined the demand for breast cancer genetic testing and counseling among Canadian women diagnosed with breast cancer under the age of 50, together with some of the factors predicting both their intentions to be tested and the degree to which they act on their intentions. Participants were 110 women under the age of 50 and comprised of two groups: 1) women diagnosed with breast cancer (BC, n = 60): and 2) an index group of unaffected women from the general population (GP, n = 50). All participants completed a survey that addressed family history of breast and other cancers, demographic variables, knowledge and attitudes about breast cancer, and genetic testing. Members of the BC group were offered genetic counseling and testing for BRCA1 and BRCA2 free of charge. Overall, 60% of participants indicated they would like the test, and 40% either did not want it or were uncertain. Seventy-two percent of women in the BC group wanted to be tested. Of these, only 49% had actually contacted the genetic counselor about testing at follow-up 3-15 months later. Intention to be tested was associated with presence of breast cancer, greater perceived benefits of testing, fewer perceived 'costs' of testing, and higher levels of concern about the risk of relatives developing breast cancer. Actual arranging to meet with the genetic counselor among women in the BC group was associated with fewer perceived costs of having the test. Results suggest a moderate level of interest in gene testing, though intention to be tested may not translate into actual uptake. Women who do choose to have the test may believe the potential 'costs' of using this new genetic technology to be relatively few. This has implications for genetic counselors in terms of providing balanced and complete information to women considering genetic testing for breast cancer susceptibility.     

Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab

PurposeThis study examined the utility of sets of single-nucleotide polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC).MethodsWe derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the Breast Cancer Family Registry and Kathleen Cuningham Consortium Foundation for Research into Familial Breast Cancer familial BC cohorts. We compared scores for women based on cancer status at baseline; 2,599 women unaffected at enrollment were followed-up for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone.ResultsThe mean PRS at baseline was 2.25 (SD, 0.35) for affected women and was 2.17 (SD, 0.35) for unaffected women from combined cohorts (P < 10^–6). During follow-up, 205 BC cases occurred. The hazard ratios for continuous PRS (per SD) and upper versus lower quintiles were 1.38 (95% confidence interval: 1.22–1.56) and 3.18 (95% confidence interval: 1.84–5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered.ConclusionIncluding BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women.     

Lifestyle influences on the association between pre-diagnostic hormone replacement therapy and breast cancer prognosis—Results from The Danish ‘Diet,Cancer and Health’ prospective cohort

ObjectivesThe association between pre-diagnostic hormone replacement therapy (HRT) and breast cancer specific mortality as well as potential influences from other lifestyle factors on the association was investigated.Study designFemale participants from the prospective cohort “Diet, Cancer, and Health” diagnosed with breast cancer (BC) were identified and their pre-diagnostic HRT use evaluated for association with tumour biology and breast cancer outcome in multivariate analysis.Main outcome measureBreast cancer specific mortality.ResultsOf the 1212 patients originally considered 1064 were included. Of these, 105 women died from breast cancer during a median follow-up of 6.3 years (range 0.2–14.3 years). In multivariate analyses women who used HRT at enrolment into the cohort study had 47% lower risk of dying from breast cancer as compared to women who had previously or never used HRT (adjusted HR: 0.53; 95% CI, 0.37–0.85). Pre-diagnostic HRT use was associated with smaller tumour size at the time of diagnosis and a higher frequency of receptor positive breast cancer. Paradoxically, a high pre-diagnostic intake of vitamin D supplements was associated with HRT use but also with a higher BC specific mortality (HR: 1.47; 95% CI, 1.07–2.00)ConclusionsHRT use at enrolment was associated with breast tumours of smaller size at the time of diagnosis and positive receptor status, and with a lower BC mortality. The found association between vitamin D from supplements and higher BC mortality warrants further exploration.     

Use of artificial neural networks in modeling associations of discriminant factors: towards an intelligent selective breast cancer screening.

In order to improve the costs/benefits ratio of breast cancer (BC) screenings, the author evaluated the performance of a back-propagation artificial neural network (ANN) to predict an outcome (cancer/not cancer) to be used as classificator. Networks were trained on data from familial history of cancer, and sociodemographic, gynecoobstetric and dietary variables. The ANN achieved up to 94.04% of positive predictive value and 97.60% of negative predictive value. Results could operate as guidelines for preselecting women who would be considered as a BC high-risk subpopulation. The procedure--not only based on age factor, but on a multifactorial basis--appears to be a promising method of achieving a more efficient detection of preclinical, asymptomatic BC cases.     

Breast cancer disparities in outcomes; unmasking biological determinants associated with racial and genetic diversity

Clinical & Experimental Metastasis - Breast cancer (BC) remains a leading cause of death among women today, and mortality among African American women in the US remains 40% higher than that of...     

Longitudinal Gompertzian analysis of breast cancer mortality in the U.S., 1962-1987: demonstration of a disorder displaying complex deterministic mortality dynamics.

Age-adjusted mortality rates for breast cancer (BC) in the United States from 1962 to 1987 were subjected to longitudinal Gompertzian analysis. Age-adjusted BC mortality rate distributions for women display two distinct Gompertzian slopes. Between age 15 and 40 years, age-adjusted BC mortality rate distributions intercepted at age 33.5 years and mortality rate (per 100,000) 5.83. Between age 50 and 85 years, age-adjusted BC mortality rate distributions intercepted at age 60.4 years and mortality rate 77.0. These two distinct Gompertzian regions correspond to the clinical and biological classification of BC into pre- and post-menopausal varieties. The observation that postmenopausal BC increases in environments conducive to survival and that premenopausal BC increases in environments that are less favorable becomes understandable when BC mortality dynamics are viewed from a competitive and deterministic perspective.     

Central European BRCA2 mutation carriers: Birth cohort status correlates with onset of breast cancer

Background

Mutations in brca1 and 2 genes lead to a significant increase in the lifetime risk of developing breast (BC) and ovarian cancer (OC). There are indications that birth cohort can influence the cancer risk in brca1 mutation carriers. Therefore, we investigated the risks for BC and OC associated with brca2 mutations in a cohort of female mutation carriers of a genetically heterogeneous Central European population.

Patients and methods

This study included 246 women in whom a functional mutation in the brca2 gene had been identified at our institution. At the time of analysis, 153 women had developed cancer (142 BC, 9 OC, 2 BC and OC). Risks were estimated using the product limit method. The log rank test was used to compare different strata.

Results

After correction for risk-reducing surgeries, the cumulative risk of developing cancer to age 70 was found to be 88% for BC (95% CI 81–95%) and 31% for OC (95% CI 17–45%). Female brca2 mutation carriers born in 1958 or later were at a significantly higher risk of developing BC at a younger age (p < 0.001), while no such age cohort-dependent correlation was found for OC.

Conclusion

The age cohort-dependent early onset in BC in women born after 1958 strongly suggests the importance of exogenous factors such as lifestyle modification while this does not seem to be the case for OC. Female brca2 mutation carriers should be counseled about their age cohort-dependent breast cancer risk.     

蛋白质指纹图谱在乳腺癌诊断与随访中的应用研究

目的:应用表面加强激光解吸电离-飞行时间质谱(SELDI-TOF-MS)和CM10蛋白质芯片检测乳腺癌患者血清蛋白质指纹图谱,筛选候选肿瘤标志物,建立、验证诊断模型并初步探讨其在术后随访监测中的价值。方法:SELDI-TOF-MS技术及CM10芯片检测63例乳腺癌和40例健康人的指纹图谱,ZJU-PDAS软件筛选标志物、建立模型,在另23例乳腺癌和20例健康人中盲法验证模型;并检测16份术后标本以探索其随访监测价值。结果:质荷比(m/z)为3.9kD和5.6kD的2个蛋白质峰(分别命名为BC1和BC2)构建的模型诊断乳腺癌灵敏度为87.30%(55/63)、特异度为95.00%(38/40);盲法验证灵敏度为95.65%(22/23)、特异度为85.00%(17/20);对不同病期患者具有相同诊断效力(P0.05)。BC1手术后表达升高;BC2手术后表达降低,且复发转移组表达高于无瘤生存组(P0.05)。结论:该方法在乳腺癌的诊断、术后随访及肿瘤标志物筛选等方面具有一定价值,值得进一步研究。     

Association between genetic variants at 9p21 locus with risk of breast cancer: A systematic review and meta-analysis

Breast cancer (BC) is the most frequent tumor in women and genetic factors are among the main risk factors contributing to this malignancy. Chromosome 9p21 contains important regulatory non-coding RNAs and is associated with multiple malignancies including BC. The current meta-analysis aimed to investigate the association between genetic variants within the 9p21 locus and risk of breast cancer. A literature search was performed using PubMed, Web of Science, Embase, MEDLINE, Scopus and Clinical key databases. Nine studies containing 23,726 subjects were eligible for the final analysis and specific odds ratios (OR) and confidence intervals (95% CI) were evaluated to assess the strength of the associations. In the pooled analysis, there was an association between the genetic variations in 9p21 locus (CDKN2A/2B) with risk of breast cancer with a standard OR of 1.22 (95% CI: 1.04–1.45, P = 0.016; random-effects model), supporting the significance of this locus as a novel risk factor for breast cancer patients. In conclusion, our results showed that 9p21 region is positively associated with risk of BC and its polymorphisms may be a candidate marker for BC susceptibility.     

Estradiol increases ER-negative breast cancer metastasis in an experimental model

Breast cancer (BC) is the most common cancer affecting women in the United States and metastatic breast cancer is the leading cause of death. The role estradiol plays in ER-positive BC is well-documented, but the way it contributes to ER-negative BC remains unclear. In the present study, we utilized an experimental model of BC metastasis into lung by injecting ER-negative murine 4T1 cells into mice via the lateral tail vein. A 56 % metastasis occurrence rate following the injection of 5 × 10³ cells was observed, thus this cell number was selected to study the potential stimulatory effect of estradiol on ER-negative BC metastasis. Female ovariectomized mice were randomized into estradiol and control groups with 16 mice per group, and estradiol pellets were implanted subcutaneously in the estradiol group. Results demonstrated that estradiol accelerated BC metastasis as indicated by bioluminescent imaging. In addition, estradiol enhanced metastatic tumor colony formation and increased the size of tumor nodules in the lungs, which were due, in part, to the increase in proliferative cells in the metastatic tumors. In vitro, estradiol increased the motility and invasion of 4T1 cells, and the stimulatory effect on cell motility was not blocked by ICI 182, 780, confirming that ER was not involved in the process. Results from the present study suggest that estradiol plays a role in ER-negative BC metastasis in whole animals.     

The impact of breast cancer on fears of exercise and exercise identity

ObjectivesLow exercise adherence is common amongst breast cancer (BC) patients. This study aimed to understand BC patients exercise identity and fears of exercise to identify barriers to exercise participation.MethodsWomen (18 years plus) currently undergoing, or completed (in remission), chemotherapy for BC, and women (18 years plus) with no cancer history completed three validated questionnaires: Exercise Identity Scale (EI), Exercise Fear Avoidance Scale (EFAS) and Fear of Physical Activity/Exercise Scale – Breast Cancer.Results86 women were included (BC: n = 51 – non-cancer: n = 35). There were no significant differences between groups when comparing overall EI (p = 0.240; d=0.127) and EFAS (p = 0.060; d=0.203) scores. BC reported significantly higher scores on specific questions related to fear during exercise (EFAS 2,3, and 5; p = <0.005). Associations were observed between EI and EFAS questionnaire scores in BC (r = ?0.342; p = 0.014), and EI scores and exercise levels in both groups (BC, r = 0.527; p = <0.001; non-cancer, r = 0.639; p = <0.001).ConclusionResults suggest women with BC may have specific concerns and fears of exercise compared to age-matched controls. Education may mitigate fears, increase exercise identity, and promote exercise uptake.Practical implicationsEducation provided by clinicians at BC diagnosis regarding the benefits and safety of exercise may help mitigate fear and promote exercise identity.     

MiR-337-3p suppresses migration and invasion of breast cancer cells by downregulating ESRP1

Breast cancer (BC) is a common malignant tumor in women, and a considerable number of studies show that aberrant expression of miRNA is correlated with BC development. By analyzing TCGA-BRCA database through bioinformatics method, this study disclosed that miR-337−3p was significantly low in BC tissue and might be a cancer inhibitor in BC. To explore the effect and potential mechanism of miR-337−3p in BC, qRT-PCR was used in this study to indicate that the expression of miR-337−3p was downregulated in BC cells. Then, the effects of miR-337−3p on BC cells were detected by western blot, Cell Counting Kit-8 (CCK-8), wound healing and Transwell assays. After upregulating miR-337−3p expression, the cell viability, migration, invasion and epithelial-mesenchymal transition (EMT) of BC cells were markedly inhibited while cell apoptosis remarkably increased. Besides, it was predicted and identified by bioinformatics analysis and dual-luciferase assay that ESRP1 was a target gene of miR-337−3p. Finally, the progression and EMT of BC cells were promoted after upregulating ESRP1 expression level. However, upregulating miR-337−3p as well as ESRP1 reduced the promotion on the malignant phenotype of BC cells. This result revealed that miR-337−3p could inhibit ESRP1 expression to perform its biological functions. In conclusion, it was illustrated in this study that miR-337−3p is a tumor-inhibitor of BC and plays its regulatory role via its downstream gene ESRP1.     

Lifestyle influences on the association between pre-diagnostic hormone replacement therapy and breast cancer prognosis—Results from The Danish ‘Diet,Cancer and Health’ prospective cohort

Objectives

The association between pre-diagnostic hormone replacement therapy (HRT) and breast cancer specific mortality as well as potential influences from other lifestyle factors on the association was investigated.

Study design

Female participants from the prospective cohort “Diet, Cancer, and Health” diagnosed with breast cancer (BC) were identified and their pre-diagnostic HRT use evaluated for association with tumour biology and breast cancer outcome in multivariate analysis.

Main outcome measure

Breast cancer specific mortality.

Results

Of the 1212 patients originally considered 1064 were included. Of these, 105 women died from breast cancer during a median follow-up of 6.3 years (range 0.2–14.3 years). In multivariate analyses women who used HRT at enrolment into the cohort study had 47% lower risk of dying from breast cancer as compared to women who had previously or never used HRT (adjusted HR: 0.53; 95% CI, 0.37–0.85). Pre-diagnostic HRT use was associated with smaller tumour size at the time of diagnosis and a higher frequency of receptor positive breast cancer. Paradoxically, a high pre-diagnostic intake of vitamin D supplements was associated with HRT use but also with a higher BC specific mortality (HR: 1.47; 95% CI, 1.07–2.00)

Conclusions

HRT use at enrolment was associated with breast tumours of smaller size at the time of diagnosis and positive receptor status, and with a lower BC mortality. The found association between vitamin D from supplements and higher BC mortality warrants further exploration.