A clinical case of diagnosis of breast cancer in patients with family history of BRCA mutations 1

BackgroundThe incidence of breast cancer is growing rapidly worldwide (1.7 million new cases and 600,000 deaths per year). Moreover, about 10% of breast cancer cases occur in young women under the age of 45. The aim of the study was to report a rare case of BRCA 1-mutated breast cancer in a young patient with multiple affected relatives. Breast cancer is due to a genetic predisposition with BRCA1 and BRCA2 representing a significant proportion of families with a very high risk of developing the disease over a lifetime of up to 50–80%.Case presentationIn this paper we report a case of a 29-year-old woman with a confirmed diagnosis of left breast carcinoma.ConclusionsMutations of the BRCA1 gene were revealed in the patient, in two of her sisters, brother and brother’s daughter.     

The aetiology and pathogenesis of human breast cancer

Whilst investigators have clearly shown that non-hereditary factors dominate the aetiology of human breast cancer, they have failed to identify quantitatively important causes, and prospects for prevention remain indeed. However, progress in epidemiological and basic research has taken place during the last few years. Current evidence suggests that breast cancer may be affected by the intra-uterine environment, that exposures during adolescence are particularly important, and that pregnancy has a dual effect on breast cancer risk: an early increase followed by long-term protection. Great variation exists in the structural development of the breast ductal system already in the newborn — and by inference in utero — and a pregnancy induces permanent structural changes in the mammary gland. We suggest that these observations fit into an aetiological model with the following key components: (1) breast cancer risk depends on the number of cells at risk, the susceptibility of individual cells to malignant transformation, and on the degree of cellular proliferation, notably cells which can act as founders of breast cancer; (2) the number of target cells is determined by the hormonal environment mainly early in life, perhaps already in utero; (3) in adult life, hormones which are non-genotoxic, increase breast cancer risk by increasing selective cell proliferation and thus number of target cells and the risk of retention of spontaneous somatic mutations; (4) while a pregnancy stimulates the growth of already malignant cells to malignant transformation (and thereby entails a short-term risk increase) the dominating long-term protection occurs due to permanent structural changes, terminal differentiation and perhaps decreased cell proliferation and carcinogen-binding in combination.     

Matrix metalloproteases and TIMPs as prognostic biomarkers in breast cancer patients treated with radiotherapy: A pilot study

Breast cancer (BC) is the most common tumour in women and one of the most important causes of cancer death worldwide. Radiation therapy (RT) is widely used for BC treatment. Some proteins have been identified as prognostic factors for BC (Ki67, p53, E‐cadherin, HER2). In the last years, it has been shown that variations in the expression of MMPs and TIMPs may contribute to the development of BC. The aim of this pilot work was to study the effects of RT on different MMPs (‐1, ‐2, ‐3, ‐7, ‐8, ‐9, ‐10, ‐12 and ‐13) and TIMPs (‐1 to ‐4), as well as their relationship with other variables related to patient characteristics and tumour biology. A group of 20 BC patients treated with RT were recruited. MMP and TIMP serum levels were analysed by immunoassay before, during and after RT. Our pilot study showed a slight increase in the levels of most MMP and TIMP with RT. However, RT produced a significantly decrease in TIMP‐1 and TIMP‐3 levels. Significant correlations were found between MMP‐3 and TIMP‐4 levels, and some of the variables studied related to patient characteristics and tumour biology. Moreover, MMP‐9 and TIMP‐3 levels could be predictive of RT toxicity. For this reason, MMP‐3, MMP‐9, TIMP‐3 and TIMP‐4 could be used as potential prognostic and predictive biomarkers for BC patients treated with RT.     

Amino acids and their roles in tumor immunotherapy of breast cancer

Breast cancer is the most commonly diagnosed cancer among women. The primary treatment options include surgery, radiotherapy, chemotherapy, targeted therapy and hormone therapy. The effectiveness of breast cancer therapy varies depending on the stage and aggressiveness of the cancer, as well as individual factors. Advances in early detection and improved treatments have significantly increased survival rates for breast cancer patients. Nevertheless, specific subtypes of breast cancer, particularly triple-negative breast cancer, still lack effective treatment strategies. Thus, novel and effective therapeutic targets for breast cancer need to be explored. As substrates of protein synthesis, amino acids are important sources of energy and nutrition, only secondly to glucose. The rich supply of amino acids enables the tumor to maintain its proliferative competence through participation in energy generation, nucleoside synthesis and maintenance of cellular redox balance. Amino acids also play an important role in immune-suppressive microenvironment formation. Thus, the biological effects of amino acids may change unexpectedly in tumor-specific or oncogene-dependent manners. In recent years, there has been significant progress in the study of amino acid metabolism, particularly in their potential application as therapeutic targets in breast cancer. In this review, we provide an update on amino acid metabolism and discuss the therapeutic implications of amino acids in breast cancer.     

Hippo信号通路在乳腺癌中的调控机制及作用

Hippo信号通路是调控器官大小和肿瘤发生发展的关键通路,近年来受到广泛的关注。TAZ/YAP作为哺乳动物中Hippo信号通路两个核心下游效应分子,通过Hippo信号通路依赖性和非依赖性的机制受到细胞内外信号的严密调控。除了参与正常乳腺组织发育,Hippo信号通路还在人乳腺癌细胞的增殖、分化、凋亡、迁移、侵袭、上皮-间质转化和干性维持等多个过程中起着关键性作用。本文总结了Hippo信号通路的调控机制和调节信号,阐述了Hippo信号通路异常在乳腺癌发生发展中的作用,并讨论了其在乳腺癌中作为治疗靶点的临床策略。     

Cytological and immunocytochemical evaluation of thyroid and breast masses in patients with a previous neoplasm: case reports

The diagnosis of secondary tumours represents one of the most important fields in the application of fine needle aspiration cytology (FNAC). We studied two patients, one with a history of breast cancer and one with a previous tumour of the thyroid, who showed a second mass, in the thyroid and in the breast, respectively, during follow up. The aim of our study was to evaluate if cytology, performed on FNAC smears, may distinguish a metastatic lesion from a second primary tumour, or if further immunocytochemistry should be performed. Our data demonstrate that, while cytology may be indicative of a second primary tumour, the histotype should be confirmed by immunocytochemical staining.     

A study of glutathione status in the blood and tissues of patients with breast cancer

Glutathione plays an important role in the antioxidant system that is required for the maintenance of the redox status of the cell, defence against free radicals and detoxification of toxic compounds. Reduced glutathione (redGSH) can be converted to oxidized glutathione (GSSG) during oxidative stress. The ratio of redGSH/total glutathione can be regarded as an index of the redox status and a useful indicator of disease risks. We conducted experiments by the capillary zone electrophoresis method to investigate the alterations of the glutathione status in the blood and tissue samples from patients with breast cancer. The results showed that the levels of redGSH, GSSG, total glutathione and the ratio of redGSH/total glutathione were significantly decreased in the blood of the patients with breast cancer compared to those of the control subjects. The levels of various forms of glutathione were lower and more pronounced in stage III. In contrast, the levels of redGSH, GSSG, total glutathione and the redGSH/total glutathione ratio in breast cancer tissues were significantly increased relative to those of the adjacent cancer-free tissues, especially in stage II. We suggest that the high redGSH levels are associated with the enhancement of cell proliferation and resistance to apoptosis in the cancer cells, and the loss of the large amount of erythrocyte redGSH may be due to increased detoxification capacities and defence against oxidative stress. We propose that redGSH should be regarded as an important biochemical parameter for detecting breast malignancy.     

DNA repair genes XRCC1 and XRCC3 polymorphisms and their relationship with the level of micronuclei in breast cancer patients

Breast cancer (BC) is the most prevalent type worldwide, besides being one of the most common causes of death among women. It has been suggested that sporadic BC is most likely caused by low-penetrance genes, including those involved in DNA repair mechanisms. Furthermore, the accumulation of DNA damage may contribute to breast carcinogenesis. In the present study, the relationship between two DNA repair genes, viz., XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) polymorphisms, and the levels of chromosome damage detected in 65 untreated BC women and 85 healthy controls, was investigated. Chromosome damage was evaluated through micronucleus assaying, and genotypes determined by PCR-RFLP methodology. The results showed no alteration in the risk of BC and DNA damage brought about by either XRCC1 (Arg399Gln) or XRCC3 (Thr241Met) action in either of the two groups. Nevertheless, on evaluating BC risk in women presenting levels of chromosome damage above the mean, the XRCC3Thr241Met polymorphism was found to be more frequent in the BC group than in the control, thereby leading to the conclusion that there is a slight association between XRCC3 (241 C/T) genotypes and BC risk in the subgroups with higher levels of chromosome damage.     

The role of EMT-related lncRNA in the process of triple-negative breast cancer metastasis

Triple-negative breast cancer (TNBC) is the most malignant and fatal subtype of breast cancer, which has characterized by negativity expression of ER, PR, and HER2. Metastasis is the main factor affecting the prognosis of TNBC, and the process of metastasis is related to abnormal activation of epithelial–mesenchymal transition (EMT). Recent studies have shown that long non-coding RNA (LncRNA) plays an important role in regulating the metastasis and invasion of TNBC. Therefore, based on the metastasis-related EMT signaling pathway, great efforts have confirmed that LncRNA is involved in the molecular mechanism of TNBC metastasis, which will provide new strategies to improve the treatment and prognosis of TNBC. In this review, we summarized many signal pathways related to EMT involved in the transfer process. The advances from the most recent studies of lncRNAs in the EMT-related signal pathways of TNBC metastasis. We also discussed the clinical research, application, and challenges of LncRNA in TNBC.     

microRNAs in breast cancer: regulatory roles governing the hallmarks of cancer

A large number of etiological factors and the complexity of breast cancers present challenges for prevention and treatment. Recently, the emergence of microRNAs (miRNAs) as cancer biomarkers has added an extra dimension to the ‘molecular signatures’ of breast cancer. Bioinformatic analyses indicate that each miRNA can regulate hundreds of target genes and could serve functionally as ‘oncogenes’ or ‘tumour suppressor’ genes, and co‐ordinate multiple cellular processes relevant to cancer progression. A number of studies have shown that miRNAs play important roles in breast tumorigenesis, metastasis, proliferation and differentiation of breast cancer cells. This review provides a comprehensive overview of miRNAs with established functional relevance in breast cancer, their established target genes and resulting cellular phenotype. The role and application of circulating miRNAs in breast cancer is also discussed. Furthermore, we summarize the role of miRNAs in the hallmarks of breast cancer, as well as the possibility of using miRNAs as potential biomarkers for detection of breast cancer.     

The role of radiotherapy in the management of nodal disease in breast cancer

The management of nodal disease in breast cancer has evolved over the last two decades. With minimalist surgical approaches for early breast cancers becoming commonplace, the question of whether radiation can replace surgery to reduce morbidity is an important question in this population, as decision making has become more complex. In more advanced disease, and in patients with significant high-risk clinical and/or pathological features, the dilemma of who should receive regional nodal irradiation has been addressed in large studies but remains controversial. In this article, we summarise and discuss the recent trials which guide modern clinical practice, as well as some of the ongoing studies which aim to address outstanding questions within the field.     

Socioeconomic status and its relation with breast cancer recurrence and survival in young women in the Netherlands

BackgroundAssociations between socioeconomic status (SES) and breast cancer survival are most pronounced in young patients. We further investigated the relation between SES, subsequent recurrent events and mortality in breast cancer patients < 40 years. Using detailed data on all recurrences that occur between date of diagnosis of the primary tumor and last observation, we provide a unique insight in the prognosis of young breast cancer patients according to SES.MethodsAll women < 40 years diagnosed with primary operated stage I-III breast cancer in 2005 were selected from the nationwide population-based Netherlands Cancer Registry. Data on all recurrences within 10 years from primary tumor diagnosis were collected directly from patient files. Recurrence patterns and absolute risks of recurrence, contralateral breast cancer (CBC) and mortality – accounting for competing risks – were analysed according to SES. Relationships between SES, recurrence patterns and excess mortality were estimated using a multivariable joint model, wherein the association between recurrent events and excess mortality (expected mortality derived from the general population) was included.ResultsWe included 525 patients. The 10-year recurrence risk was lowest in high SES (18.1%), highest in low SES (29.8%). Death and CBC as first events were rare. In high, medium and low SES 13.2%, 15.3% and 19.1% died following a recurrence. Low SES patients had shorter median time intervals between diagnosis, first recurrence and 10-year mortality (2.6 and 2.7 years, respectively) compared to high SES (3.5 and 3.3 years, respectively). In multivariable joint modeling, high SES was significantly related to lower recurrence rates over 10-year follow-up, compared to low SES. A strong association between the recurrent event process and excess mortality was found.ConclusionsHigh SES is associated with lower recurrence risks, less subsequent events and better prognosis after recurrence over 10 years than low SES. Breast cancer risk factors, adjuvant treatment adherence and treatment of recurrence may possibly play a role in this association.     

Comparison of the roles of estrogens and androgens in breast cancer and prostate cancer

Breast cancer (BC) and prostate cancer (PC) are the second most common malignant tumors in women and men in western countries, respectively. The risks of death are 14% for BC and 9% for PC. Abnormal estrogen and androgen levels are related to carcinogenesis of the breast and prostate. Estradiol stimulates cancer development in BC. The effect of estrogen on PC is concentration-dependent, and estrogen can regulate androgen production, further affecting PC. Estrogen can also increase the risk of androgen-induced PC. Androgen has dual effects on BC via different metabolic pathways, and the role of the androgen receptor (AR) in BC also depends on cell subtype and downstream target genes. Androgen and AR can stimulate both primary PC and castration-resistant PC. Understanding the mechanisms of the effects of estrogen and androgen on BC and PC may help us to improve curative BC and PC treatment strategies.     

Inhibition of the autophagic flux by salinomycin in breast cancer stem-like/progenitor cells interferes with their maintenance

Breast cancer tissue contains a small population of cells that have the ability to self-renew; these cells are known as cancer stem-like cells (CSCs). We have recently shown that autophagy is essential for the tumorigenicity of these CSCs. Salinomycin (Sal), a K⁺/H⁺ ionophore, has recently been shown to be at least 100 times more effective than paclitaxel in reducing the proportion of breast CSCs. However, its mechanisms of action are still unclear. We show here that Sal blocked both autophagy flux and lysosomal proteolytic activity in both CSCs and non-CSCs derived from breast cancer cells. GFP-LC3 staining combined with fluorescent dextran uptake and LysoTracker-Red staining showed that autophagosome/lysosome fusion was not altered by Sal treatment. Acridine orange staining provided evidence that lysosomes display the characteristics of acidic compartments in Sal-treated cells. However, tandem mCherry-GFP-LC3 assay indicated that the degradation of mCherry-GFP-LC3 is blocked by Sal. Furthermore, the protein degradation activity of lysosomes was inhibited, as demonstrated by the rate of long-lived protein degradation, DQ-BSA assay and measurement of cathepsin activity. Our data indicated that Sal has a relatively greater suppressant effect on autophagic flux in the ALDH⁺ population in HMLER cells than in the ALDH⁻ population; moreover, this differential effect on autophagic flux correlated with an increase in apoptosis in the ALDH⁺ population. ATG7 depletion accelerated the proapoptotic capacity of Sal in the ALDH⁺ population. Our findings provide new insights into how the autophagy-lysosomal pathway contributes to the ability of Sal to target CSCs in vitro.     

PTPH1 immunohistochemical expression and promoter methylation in breast cancer patients from India: A retrospective study

Protein Tyrosine Phosphatase H1/Protein Tyrosine Phosphatase Non receptor Type 3 (PTPH1/PTPN3) is upregulated and/or mutated in glioma, ovarian, gastric, and colorectal cancers. Previous studies have documented that PTPH1-associated breast cancers exhibit enhanced sensitivity to tamoxifen and tyrosine kinase inhibitors through dephosphorylation of ER and epidermal growth factor receptor, respectively. Owing to the key role that PTPH1 plays as a biomarker in predicting the response of chemotherapeutic drugs and lack of studies on Indian breast cancer patients, the present study investigated PTPH1 protein expression and its relationship to clinical features, ER/PR/HER2/neu statuses, and methylation of promoter in breast cancer tissues (n = 67) among Indian population by immunohistochemistry and methylation specific polymerase chain reaction. PTPH1 expression was upregulated in 58.21% (39/67) and downregulated in the rest of tumor specimens, and it correlated with ER, PR, and HER2/neu statuses with p values of <0.0001, 0.0113, and 0.0448, respectively. Additionally, we found that the 2 kb region upstream of PTPH1 gene harbored CpG sites within, and was ubiquitously methylated in breast cancer (n = 13), colon cancer tissue (n = 1), uterine cancer tissue (n = 1), normal breast tissue (n = 1) in addition to Hela and MCF7 cell lines. In conclusion, our data showed a strong correlation of the PTPH1 status with the ER and ubiquitous nature of PTPH1 promoter methylation at specific CpG sites irrespective of cancer types and protein expression. Our findings underscore the clinical relevance of PTPH1 expression in Indian patients and warrant additional studies to explore the importance of ubiquitously methylated promoter at specific CpG sites in upstream of the PTPH1 gene.     

Antioxidant status and lipid peroxidation in the blood of breast cancer patients of different ages

Oxidative stress is considered to be implicated in the pathophysiology of breast cancers. In this study we investigated the level of oxidative stress and antioxidant (AO) status in the blood of breast cancer patients of different ages. The level of lipid hydroperoxides (LP) was measured in blood plasma and the activities of copper, zinc superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) enzymes, as well as the level of total glutathione (GSH) and CuZnSOD protein were measured in blood cells of breast cancer patients and age-matched healthy subjects. Our results showed that breast carcinoma is related to increase of lipid peroxidation in plasma with concomitant decrease of AO defense capacity in blood cells, which becomes more pronounced during aging of the patients. Suppression of CuZnSOD activity related to breast cancer is most likely caused by decreased de novo synthesis of this enzyme. Similar patterns of suppression in CuZnSOD and CAT activities related to aging were recorded both in controls and patients. Age-related decrease in CuZnSOD activity seems not to be caused by altered protein levels of this enzyme. Suppression of AO enzymes associated with breast cancer and aging is most likely the cause of increased levels of reactive oxygen species (ROS). Our results indicate significant role of oxidative-induced injury in the breast carcinogenesis, particularly during the later stages of aging. Overall, our data support the importance of endogenous AOs in the etiology of breast cancer across all levels of predicted risk.