Effects of Omega-3 Fatty Acids on Progestin Stimulation of Invasive Properties in Breast Cancer

Clinical studies have shown that progestins increase breast cancer risk in hormone replacement therapy, while we and others have previously reported that progestins stimulate invasive properties in progesterone receptor (PR)-rich human breast cancer cell lines. Based on others?? reports that omega-3 fatty acids inhibit metastatic properties of breast cancer, we have reviewed the literature for possible connections between omega-3 fatty-acid-driven pathways and progestin-stimulated pathways in an attempt to suggest theoretical mechanisms for possible omega-3 fatty acid inhibition of progestin stimulation of breast cancer invasion. We also present some data suggesting that fatty acids regulate progestin stimulation of invasive properties in PR-rich T47D human breast cancer cells, and that an appropriate concentration of the omega-3 fatty acid eicosapentaenoic acid inhibits progestin stimulation of invasive properties. It is hoped that focus on the inter-relationship between pathways by which omega-3 fatty acids inhibit and progestins stimulate breast cancer invasive properties will lead to further in vitro, in vivo, and clinical studies testing the hypothesis that omega-3 fatty acids can inhibit progestin stimulation of invasive properties in breast cancer, and ameliorate harmful effects of progestins which occur in combined progestin?Cestrogen hormone replacement therapy.     

Protective Effect of Omega-3 Fatty Acids in Fish Consumption Against Breast Cancer in Asian Patients: A Meta-Analysis

Objective: This systematic review and meta-analysis was performed to determine the protective effect of omega-3fatty acids in fish consumption against breast cancer in Asian patients. Methods: The authors conducted a meta-analysisof published research articles on protective effect of omega-3 fatty acids in fish consumption against breast cancer inAsian patients published between January 2000 and July 2018 in online database of PubMed, ProQuest and EBSCO.Pooled odds ratios (OR) were calculated by using fixed and random-effect models. Publication bias was visuallyevaluated by using funnel plots and statistically assessed in Egger’s and Begg’s tests. Data were processed by ReviewManager 5.3 (RevMan 5.3) and Stata version 14.2 (Stata Corporation). Results: This study reviewed 913 articles.There were 11 studies which conducted systematic review then continued by meta-analysis of relevant data with totalnumber of samples were 130,365 patients. The results showed there was protective effect of omega-3 fatty acids in fishconsumption against breast cancer in Asian patients (OR = 0.80 [95% CI 0.73-0.87, p <0.00001]). There was not anystudy with significant publication bias included. Conclusion: This analysis confirmed the protective effect of omega-3fatty acids in fish consumption against breast cancer in Asian patients.     

Prognostic Factors for Breast Cancer: an Immunomorphological Update

The prognostic variability recorded within homogeneous groups of patients for anatomo-clinical disease stages has led to a more detailed biological characterization of breast cancer. Recently, the attention of the scientific community has focused on the role of tumor-infiltrating lymphocytes (TILs). Therefore, the need of an in-depth immunomorphological characterization of TILs has been emerged. The presence of TILs has been retrospectively investigated in 113 female cases of ductal carcinoma. An immunohistochemical investigation with CD3, CD4, CD8, CD20, CD56, granulysin, perforin-1, granzyme-B and TIA-1 was performed according to the standard procedures on all 17 cases with TILs evidence. TILs consisted of T and B lymphocytes: the prevalent population showed a T immunoprofile with a CD8-immunopositive killer subpopulation (Tk), close-linked to carcinomatous cells, and a CD4-immunopositive helper subpopulation (Th), inside the tumor. A time sequence (firstly T, then B) has been disclosed. Granulysin, perforin, granzyme-B and TIA-1 were expressed by Tk cells. The activated Tk cells secrete these mediators as a result of the binding to the tumor target cell, causing its lytic planned death. The cytotoxicity supported by Tk cells appears an important favorable prognostic factor. Therefore, a graduation system for TILs in breast cancer has been here proposed (absent, non-brisk, brisk).     

Neoadjuvant Therapy for Breast Cancer: State of the Science and Future Directions

Systemic neoadjuvant chemotherapy has long been known to confer clinical benefits for breast cancer patients by downstaging inoperable disease or providing those with operable disease the opportunity for breast conservation, without compromising risk of recurrence. In recent years, its benefits have broadened as it has become a pivotal platform for clinical research, providing new prognostic and predictive insights into in vivo response to therapy and long-term outcomes. The use of neoadjuvant chemotherapy in the research setting has expanded our knowledge of heterogeneity in tumor biology and chemosensitivity and provided insights into the relationships between molecular signatures of tumors, pathologic complete response (pCR), and long-term outcomes. This has provided opportunities to specifically select patients who might benefit from novel therapies and test these in a more efficient manner. Despite these major advancements, however, the majority of patients do not attain a pathologic complete response with systemic neoadjuvant chemotherapy. This review describes the standard of care for systemic neoadjuvant therapy for breast cancer and discusses current management controversies and ongoing clinical trials designed to increase the proportion of patients who currently achieve a pCR.     

Treatment of Bone Metastases in Breast Cancer: an Update

Bone is the most common site of breast cancer metastases. When breast cancer has metastasized to bone, it is considered an incurable disease. Osseous metastases are associated with significant morbidities including pain, pathological fractures, hypercalcemia of malignancy, and spinal cord compression. In this setting, the palliative goals of care include preventing skeletal related events, managing complications, reducing bone pain, and improving quality of life. Antiresorptive agents such as bisphosphonates have been the mainstay of bone-directed treatment, along with radiation therapy, and surgery. Most recently, RANKL-inhibitors have become another tool in the treatment of bone metastases. This review discusses bone-modifying agents and other targeted interventions in breast cancer patients with skeletal metastases.     

Intake of Freshwater Fish and Associated Fatty Acids and Risk of Breast Cancer

To investigate the association between intake of freshwater fish and their fatty acids and the risk of breastcancer in Chinese women, we conducted a case-control study with 669 cases and 682 population-based controlsin Jiangsu Province of China. A structured questionnaire was used to elicit detailed information. Unconditionallogistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Totalfreshwater fish intake was linked to decrease in the adjusted OR for breast cancer, but without dose-dependence.Analyses by freshwater fish species showed that consumption of black carp and silver carp was inversely relatedto breast cancer risk, with adjusted-ORs for the highest intake category of black carp (≥500g/month) of 0.54(95%CI=0.33-0.92; P trend<0.002) and for silver carp (≥1000g/month) of 0.19 (95%CI=0.11-0.33; P trend<0.001).In contrast, consumption of crucian carp was positively related to breast cancer risk, with an adjusted OR forthe highest intake category (≥1000g/month) of 6.09 (95%CI=3.04-12.2; P trend<0.001). Moderate intakes of SFA,PUFA, n3-PUFA and n6-PUFA from freshwater fish may decrease the risk of breast cancer among premenopausalwomen. The findings of this study suggest that intake of freshwater fish and their fatty acids may modify risk ofbreast cancer, and that different species of freshwater fish could have a different actions on breast cancer risk.Future epidemiologic studies are needed to know the effects of freshwater fish intake on breast cancer risk andthe cause of these effects.     

Update on Phase I/II Breast Cancer Prevention Trials

The greatest success in breast cancer prevention has been with two agents, tamoxifen and raloxifene, both of which are approved by the US Food and Drug Administration (FDA) for the risk reduction of invasive breast cancer in high-risk women. However, these agents are only effective in preventing a certain percentage of estrogen receptor–positive disease. New agents are needed to prevent invasive breast cancer in a broader population of women. Phase I/II clinical trials are conducted with the intent of investigating agent efficacy via surrogate endpoint biomarkers. They also allow us to refine the population that may benefit from a given intervention. In this article, we review the important components of early phase trials including study design, cohort, surrogate endpoint biomarkers, and the challenges of recruiting to prevention trials. We discuss some early-phase trials for which results have recently been reported at meetings or through publications, as well as those trials that have recently been opened.     

Prevention of Tamoxifen-related Nonalcoholic Fatty Liver Disease in Breast Cancer Patients

Background

Tamoxifen is commonly used to prevent breast cancer recurrence. Studies have confirmed the association between tamoxifen and nonalcoholic fatty liver disease (NAFLD), with the results indicating the need for aggressive management of this side effect. We assessed the potential risk factors for and identified the possible protective factors of tamoxifen-related fatty liver.

共轭三烯酸对乳腺癌细胞的增殖抑制和凋亡诱导作用

目的:探讨共轭三烯酸(TCLA)对乳腺癌细胞的增殖抑制、凋亡作用及其作用机制.方法:用TCLA处理人正常肝细胞(LO2)及乳腺癌细胞(MCF-7),用细胞增殖试验(MTT法)、克隆形成试验、EdU掺入试验研究TCLA对人正常肝细胞和乳腺癌细胞的增殖抑制作用;吖啶橙/溴乙啶(AO/EB)染色检测细胞凋亡;流式细胞术检测TCLA对细胞周期的影响;RT-PCR检测凋亡相关基因PPAR-γ、P53、CASPASE-3 mRNA表达.结果:用TCLA处理后,肿瘤细胞增殖活性降低(P<0.05),半效抑制浓度(IC50)为50 μmol,呈时间-剂量-效应关系;克隆形成下降(P<0.05)亦呈时间-剂量-效应关系;EdU标记指数降低(P<0.05),AO/EB染色凋亡细胞增多(P<0.05),细胞周期分布改变,凋亡指数显著增加(P<0.01),S期细胞显著减少(P<0.05);RT-PCR检测RT.PCR检测凋亡相关基因PPAR-γ(P<0.05)、P53(P<0.05)、CASPASE-3(P<0.01)mRNA表达均比对照组显著增加.结论:TCLA对乳腺癌细胞具有抑制增殖和诱导凋亡作用,其作用机理可能与抑制DNA合成、细胞周期阻滞、上调凋亡相关基因PPAR3γ、P53、CASPASE-3表达有关.     

ω-3多不饱和脂肪酸对人胃癌BGC-823细胞PGE2、SOD和MDA的影响

目的：观察不同浓度ω-3多不饱和脂肪酸（EPA、DHA）对人胃癌BGC-823细胞存活情况、PGE2和脂质过氧化的影响。方法：采用MTF法测定肿瘤细胞存活率，酶联免疫吸附竞争法测定PGE2浓度，黄嘌呤氧化酶法测定总SOD活力，TBA法测定MDA含量。结果：30μg／ml和45μg／ml的EPA或DHA可显著降低肿瘤细胞存活率（P〈0．001），细胞PGE2浓度和总SOD活力明显下降（P〈0．05）、而MDA含量明显升高（P〈0．05）。结论：ω-3多不饱和脂肪酸可通过PGE2代谢和脂质过氧化作用抑制人胃癌BGC-823细胞的生长。     

ω-3多不饱和脂肪酸对肿瘤细胞侵袭转移的影响及机制研究进展

摘 要：侵袭与转移是恶性肿瘤的特征性生物学行为,是一个复杂的、多步骤的癌细胞与宿主细胞相互作用的连续过程。ω-3 多不饱和脂肪酸作为被广泛研究的免疫营养物质,不仅在调节机体免疫功能、脂质代谢等方面有着重要作用,而且在肿瘤预防和治疗方面也有着重要作用。 研究表明,ω-3 多不饱和脂肪酸还能诱导多种肿瘤细胞凋亡,并能够在一定程度上抑制其侵袭和转移。文章就ω-3 多不饱和脂肪酸对肿瘤细胞侵袭转移的作用及其机制进行综述。     

Growth of Human Colon Cancer Cells in Nude Mice is Delayed by Ketogenic Diet With or Without Omega-3 Fatty Acids and Medium-chain Triglycerides

Background: Tumors are largely unable to metabolize ketone bodies for energy due to various deficienciesin one or both of the key mitochondrial enzymes, which may provide a rationale for therapeutic strategies thatinhibit tumor growth by administration of a ketogenic diet with average protein but low in carbohydrates andhigh in fat. Materials and Methods: Thirty-six male BALB/C nude mice were injected subcutaneously with tumorcells of the colon cancer cell line HCT116. The animals were then randomly split into three feeding groups andfed either a ketogenic diet rich in omega-3 fatty acids and MCT (MKD group; n=12) or lard only (LKD group;n=12) or a standard diet (SD group; n=12) ad libitum. Experiments were ended upon attainment of the targettumor volume of 600 mm3 to 700 mm3. The three diets were compared for tumor growth and survival time(interval between tumor cell injection and attainment of target tumor volume). Results: The tumor growth inthe MKD and LKD groups was significantly delayed compared to that in the SD group. Conclusions: Applicationof an unrestricted ketogenic diet delayed tumor growth in a mouse xenograft model. Further studies are neededto address the mechanism of this diet intervention and the impact on other tumor-relevant parameters such asinvasion and metastasis.     

Relevance of Breast Cancer Cell Lines as Models for Breast Tumours: An Update

The number of available breast cancer cell (BCC) lines is small, and only a very few of them have been extensively studied. Whether they are representative of the tumours from which they originated remains a matter of debate. Whether their diversity mirrors the well-known inter-tumoural heterogeneity is another essential question. While numerous similarities have long been found between cell lines and tumours, recent technical advances, including the use of micro-arrays and comparative genetic analysis, have brought new data to the discussion. This paper presents most of the BCC lines that have been described in some detail to date. It evaluates the accuracy of the few of them widely used (MCF-7, T-47D, BT-474, SK-BR-3, MDA-MB-231, Hs578T) as tumour models. It is concluded that BCC lines are likely to reflect, to a large extent, the features of cancer cells in vivo. The importance of oestrogen receptor-alpha (gene ESR1 ) and Her-2/ neu ( ERBB2 ) as classifiers for cell lines and tumours is underlined. The recourse to a larger set of cell lines is suggested since the exact origin of some of the widely used lines remains ambiguous. Investigations on additional specific lines are expected to improve our knowledge of BCC and of the dialogue that these maintain with their surrounding normal cells in vivo.     

Anti-Angiogenic Strategies in Breast Cancer: An Update

Angiogenesis plays a role in primary tumor growth and metastatic potential of breast cancer, and within the past decade, the development of angiogenesis inhibitors has been a significant focus of clinical research efforts. Multiple studies to date have confirmed a role for bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with chemotherapy in the treatment of metastatic breast cancer. Efforts to determine the efficacy of second-generation VEGF receptor antagonists in breast cancer patients are ongoing. In addition, trials are underway to investigate potential synergy between anti-angiogenic agents and other classes of breast cancer therapeutics and to examine the efficacy of angiogenesis inhibition in nonmetastatic disease. Preliminary work evaluating predictors of response to therapy, including serologic biomarkers, class-effect toxicity, or dynamic radiologic change, and pharmacogenetics, has been promising; however, future study is critical to best identify the patient population most likely to benefit from anti-angiogenic therapy.     

乳腺癌防治工作浅谈

该文介绍了近年来乳腺癌领域几个热点问题如普查，定位活检，保乳治疗，前哨淋巴结活检，综合治疗和乳房重建的研究进展。     

Lifestyle Interventions for Breast Cancer Prevention

Purpose of Review

One in eight women in the USA will develop breast cancer in her lifetime. Despite established efficacy, the use of pharmacotherapy for breast cancer prevention is limited by concerns over toxicities that may negatively influence quality of life. Additional interventions for breast cancer prevention are needed.

Recent Findings

There is emerging evidence from observational studies that obesity, physical inactivity, sedentary behavior, and dietary patterns are associated with breast cancer risk. Randomized trials are necessary to provide unbiased efficacy estimates of lifestyle changes on breast cancer risk, but such trials require a large sample size, long-term follow-up, and substantial financial investment. One approach to manage these barriers is to leverage recent advances in precision prevention to identify high-risk study participants to reduce sample size or shorten length of follow-up.

Summary

Precision prevention approaches may accelerate the translation of epidemiologic discoveries into proven population-based breast cancer prevention interventions.

     

Breast Reconstruction in the Setting of Surgical Prevention for Breast Cancer

Purpose of Review

Breast reconstruction after prophylactic mastectomy is an important component of the surgical prevention of breast cancer. Women who undergo bilateral prophylactic mastectomy view reconstruction as part of their treatment and the choice to pursue a contralateral mastectomy is influenced by the availability of reconstruction.

Recent Findings

There has been increased data available on both medical outcomes and patient-reported outcomes in reconstruction after mastectomy. This review of recent literature includes trends and outcomes with contralateral and bilateral prophylactic mastectomy with reconstruction, discussion of outcomes in implant and autologous tissue-based reconstruction, advancements in pre-pectoral implant placement, and new techniques of simultaneous mastectomy with reconstruction combined with gynecologic risk-reducing surgery.

Summary

Choice of reconstruction after prophylactic mastectomy is based on patient factors, availability of specialist services, and patient preference. Informed discussion with patients, plastic surgery, surgical oncology, and gynecology is necessary to determine the best option for each patient.

     

Aspirin and Breast Cancer Prevention

Over the past decade, breast cancer chemoprevention has made substantial progress, particularly with selective estrogen receptor modulators and aromatase inhibitors. A new generation of chemopreventive agents modulating the non-endocrine biochemical pathways has been studied so far, including the 100-year-old drug aspirin. Commonly known as pain-reliever, aspirin may also influence breast carcinogenesis through a number of mechanisms, including decreased production of prostaglandins, which can inhibit angiogenesis and inhibit apoptosis, inhibition of the cyclo-oxygenase enzymatic pathways and stimulation of the AMPk pathway leading to decreased proliferation and increased autophagy. Long-term follow-up of randomized trials of aspirin in prevention of vascular events showed that daily aspirin reduced the incidence of colorectal cancer and several other cancers, including a borderline effect on breast cancer incidence. In the present review, we discuss the potential role aspirin in breast cancer prevention comparing data from observational studies with those from the randomized trials.     

PARP Inhibitors for the Treatment and Prevention of Breast Cancer

Poly (ADP-ribose) polymerase (PARP) inhibitors, a novel class of drugs that target tumors with DNA repair defects, have received tremendous enthusiasm. Early preclinical studies identified BRCA1 and BRCA2 tumors to be highly sensitive to PARP inhibitors as a result of homologous recombination defect. Based on this premise, PARP inhibitors have been tested in early phase clinical trials as a single agent in BRCA1 or BRCA2 mutation carriers and in combination with chemotherapy in triple-negative breast cancer patients. For high-risk populations, use of PARP inhibition as a prevention agent has been postulated, but no robust preclinical or clinical studies exist yet. We review the preclinical and clinical studies in treatment of breast cancer and rationale for use of PARP inhibitors as a prevention agent for high-risk populations. Of significance, PARP inhibitors vary significantly in mechanism of action, dosing intervals, and toxicities, which are highlighted in this review.