Matrix metalloproteinase expression in breast cancer

BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated as possible mediators of invasion and metastasis in some cancers. Our objective was to investigate which MMPs were constitutively expressed in breast tumor cells versus those that could be up-regulated by a number of agents known to affect MMP expression in other cell systems. METHODS: We evaluated expression of MMPs 1-16 in breast tumor cell lines MDA-MB-231, T47D, and MCF-7 using semiquantitative RT-PCR and gelatin zymography. Exposure to 12-O-tetradecanoylphorbal-3-acetate (TPA), concanavalin-A (Con-A), the fibronectin-mimetic peptide GRGDSP (RGD), extracellular matrix (ECM) components, and anti-integrin antibodies was used to test for possible MMP up-regulation. Mitogen-activated protein kinase inhibitors (MAPK-I) were used to evaluate signal transduction pathways and regulation of MMP expression. RESULTS: MMPs 1, 2, 7-11, 13, 14, and 16 were constitutively expressed in some tumor cell lines but not in normal breast epithelial cells. Administration of TPA, Con-A, and RGD increased the expression of MMPs 1, 2, 9, and 10. No MMP up-regulation was seen in MDA-MB-231 or MCF-7 after exposure to ECM components or after exposure to anti-integrin antibodies. MAPK-I had no effect on constitutive MMP expression but reduced or abolished the TPA up-regulation of MMP-9 in MDA-MB-231 and MCF-7. CONCLUSIONS: Breast tumor cell lines constitutively express a number of MMPs. Because MMP expression can be up-regulated by Con-A, the fibronectin-mimetic peptide RGD, and TPA while being susceptible to inhibition by MAPK antagonists, MAPK signaling appears to play a role in this expression.     

The role of circulating extracellular vesicles in breast cancer classification and molecular subtyping

Currently, tumor biopsies are used for breast cancer molecular subtyping. Biopsies are associated with various pathological changes and are thought to contribute to the dissemination of tumor cells. Extracellular vesicles shed by tumor cells into circulation exhibit the molecular signature of the parent cells. Herein, we show that proteomic analysis of circulating EV can discriminate BC patients from healthy subjects and indicate stage of the disease. Also, we performed a correlation between the BC molecular subtype using plasma EV and immunohistochemistry of tumor biopsies. Circulating EV may represent a useful, non‐invasive tool to study the molecular makeup of BC tumors.     

High dose fractionated ionizing radiation inhibits prostate cancer cell adhesion and beta(1) integrin expression

BACKGROUND: The effect of ionizing radiation on extracellular matrix (ECM)-mediated cellular functions is an important area of research for translational science. Mechanisms of tumor cell ability to proliferate, migrate, and survive appear dependent on integrin-mediated adhesion to the ECM; however, the exact role therapeutic radiation plays in altering signaling pathways and promoting cell death within remains less well established. METHODS: To examine these effects on prostate carcinoma cell lines, cells were irradiated at sub-lethal doses. We have studied two human prostate cancer cell lines (PC3 and DU-145) irradiated with different fractionated radiation schedules. Three groups were compared to non-irradiated controls. Group A was given a single dose of 5 Gy. Group B was given 5 Gy the first week and then 10 Gy the second week for a total of 15 Gy. Group C was given 5 Gy the first week, and then 10 Gy the second and third week for a total of 25 Gy. Cells were analyzed at their prescribed total dose. At 48 hr post irradiation, cells were detached from culture dishes and were subsequently used for adhesion assays and immunoblotting analysis. RESULTS: Our findings revealed that two prostate carcinoma cell lines, PC3 and DU-145, had a reduced cellular adhesion to fibronectin (FN) compared to the non-irradiated control groups. Both prostate cancer cell lines showed decreased adhesion to FN and reduced beta(1) integrin protein levels at a total dose of 25 Gy, but not at the doses of 15 and 5 Gy. In a parallel analysis, at the maximum total dose of 25 Gy, both PC3 and DU-145 demonstrated a significant decrease in cell proliferation. CONCLUSIONS: High dose radiation treatment of prostate cancer cell lines inhibits integrin expression. Our study suggests that promoting a synergistic decrease in adhesion could bring additional therapeutic benefit to patients treated with radiation therapy.     

Influence of non-volatile anesthetics on the migration behavior of the human breast cancer cell line MDA-MB-468

BACKGROUND: Anesthetic agents are known to influence functions of the immune system. Anesthetic drugs also support cancer progression by suppressing the activity of immune cells. In breast carcinoma an increase in expression of peripheral-type benzodiazepine receptors (PBR) and the gamma aminobutyl acid (GABA) level has been discovered. Therefore, an investigation of a direct influence of GABA-A agonist propofol, GABA-A and PBR-agonist etomidate, and the local anesthetic drug lidocaine, which can also bind to the GABA-A receptor and PBR, on migration of breast carcinoma cells was performed. METHODS: MDA-MB-468 cells were incubated with anesthetic agents using clinically relevant concentrations (propofol 3, 6, 9 mg/l, etomidate 2, 3, 4 mg/l, and lidocaine 1.25, 2.5, 5 mg/l). Locomotion was investigated in a three-dimensional collagen matrix using time-lapse video microscopy and computer-assisted cell-tracking. RESULTS: The percentage of migrating cells (57.4+/-1.9) as well as the velocity (0.22+/-0.09 microm/min) and distance migrated (89.4+/-66.8 microm/10 h) increased in the presence of propofol in a dose-dependent manner (up to 74.4+/-7.5, 0.30+/-0.09, 143.8+/-89.1, respectively) compared with the long chain triglyceride (LCT) control. In contrast, no influence of etomidate on the number of migrating cells could be observed. The velocity and distance migrated at 3 and 4 mg/l were found to be statistically significantly enhanced. Treatment with lidocaine caused an increase in the percentage of migrating cells (up to 75.0+/-5.6) in velocity dose dependently (up to 0.33+/-0.06) and in distance migrated (up to 151.5+/-92.9). CONCLUSION: These results show that different anesthetic drugs are able to modulate the migratory machinery of human breast carcinoma cells in vitro.     

Inhibition by uraemic sera of CD4+ T-cell adhesion to extracellular matrix components

BACKGROUND.: T-cell-mediated immune responses are impaired in patients withchronic renal failure. The migration, proliferation, differentiation,biological functioning, and interaction with other T cells aremediated by cell surface adhesion proteins, which include integrins. METHODS.: To elucidate how uraemia can impair T-cell-mediated responsesin vivo, the effects of sera from uraemic patients on T-cellproliferation and adhesion to extracellular matrix (ECM) componentswere examined. RESULTS.: Preincubation of human CD4⁺ T cells with sera from undialysedand dialysed (haemodialysis or peritoneal dialysis) uraemicpatients inhibited the capacity of the cells to be stimulatedby phytohaemmagglutinin and by anti-CD3 monoclonal antibodyplus immobilized fibronectin (FN). Sera from uraemic and dialysedpatients, but not from healthy individuals, inhibited significantly,and in a dose-dependent fashion, human CD4⁺ T cell adhesionto immobilized FN and laminin (LN). The degree of inhibitionof adhesion was similar whether the sera were continuously present,even during the adhesion assay, or removed by washing. The adhesioninhibiting capacity of the uraemic sera was not due to modificationof the expression of ß1 integrins on the surfacesof the T cells. CONCLUSIONS.: These results suggest that uraemia can impair the proliferativecapacity and adhesion of immune cells, and thus may affect normalimmune processes and contribute to the overall immune deficiencyobserved in patients with renal failure.     

Tissue marker migration after MRI‐guided breast biopsy: Migration frequency and associated factors

The purpose of this study was to determine the frequency and associated risk factors contributing to immediate tissue marker migration in patients undergoing MRI‐guided breast biopsy and to evaluate how often tissue marker migration altered clinical management. Between July 2010 and May 2015, we retrospectively reviewed all MRI‐guided breast biopsies at our institution for tissue marker migration. Migration was defined as final position of the tissue marker >10 mm from the target site based on the expected location of the MRI finding on postprocedure mammogram. Factors associated with migration were analyzed using Fisher's exact test and Chi‐squared test, with P < .05 considered statistically significant. A total of 278 patients underwent 298 MRI‐guided biopsies. Migration occurred in 42/298 biopsies (14%). Almost entirely fat fibroglandular tissue was identified as an independent risk factor for tissue marker migration, occurring in 6/16 (38%), compared to 36/262 (14%) for the other fibroglandular tissue categories (P = .03). Biopsy target size was significantly associated with clip migration, occurring in 25/114 (22%) lesions <10 mm in size vs 17/184 (9%) for larger lesions (P = .003). Clinical management was affected by clip migration in 6/42 cases (14%) with one requiring ultrasound‐guided biopsy cavity marker placement and five requiring biopsy cavity wire localization. Radiologists must be vigilant in assessing for clip migration as it is not an infrequent complication. Given migration may change clinical management and require altered procedures for localization of the biopsy cavity, the possibility of clip migration should be included in informed consent.     

乳腺癌术后一期假体置入乳房再造与美学塑形

目的:探讨如何将乳房美学运用于乳腺癌术后一期假体置入乳房再造,以便获得良好的外观效果。方法:实施一期假体置入乳房再造时,注重把修复再造和美学塑形结合起来,手术要点:向下游离胸大肌止点及部分腹直肌前鞘深面,以便形成与健侧基本对称的乳房下皱襞;外侧游离前锯肌,形成前锯肌瓣,并与胸大肌外缘缝合,使乳房假体置于完整的肌后腔隙,既可有效避免假体移位,又可突显乳房外侧弧度美。结果:21例乳腺癌患者应用此方法行一期假体置入乳房再造,优14例,良6例,一般1例。优良率为95.2%。结论:实施一期假体置入乳房再造时,只有将修复再造和美学塑形结合起来,才能再造出具有良好外形和质感的乳房,使患者满意。     

乳腺癌相关microRNA的研究进展

MicroRNAs是一类内源性稳定的非编码小分子RNA，在基因转录后水平调控细胞的增殖、凋亡和分化相关的基因表达，与肿瘤的发生和发展密切相关。本文综述了乳腺癌相关的microRNA，如何通过调控目标基因的表达以控制乳腺癌的发展。     

Male breast cancer: management and follow-up recommendations

National Comprehensive Cancer Network (NCCN) guidelines for female breast cancer treatment and surveillance are well established, but similar guidelines on male breast cancers are less recognized. As an NCCN institution, our objective was to examine practice patterns and follow-up for male breast cancer compared to established guidelines for female patients. After Institutional Review Board approval, a prospective breast database from 1990 to 2009 was queried for male patients. Medical records were examined for clinico-pathological factors and follow-up. The 5-year survival rates with 95% confidence intervals were estimated using Kaplan-Meier method and Greenwood formula. Of the 19,084 patients in the database, 73 (0.4%) were male patients; 62 had complete data. One patient had bilateral synchronous breast cancer. The median age was 68.8 years (range 29-85 years). The mean/median invasive tumor size was 2.2/1.6 cm (range 0.0-10.0 cm). All cases had mastectomy (29 with axillary node dissection, 23 with sentinel lymph node biopsy only, 11 with sentinel node biopsy followed by completion axillary dissection). Lymph node involvement occurred in 25/63 (39.7%). Based on NCCN guidelines, chemotherapy, hormonal therapy, and radiation are indicated in 34 cases, 62 cases, and 14 cases, respectively. Only 20/34 (59%) received chemotherapy, 51/62 (82%) received hormonal therapy, and 10/14 (71%) received post-mastectomy radiation. Median follow-up was 26.2 months (range: 1.6-230.9 months). The 5-year survival estimates for node positive and negative diseases were 68.5% and 87.5%, respectively (p = 0.3). Despite the rarity of male breast cancer, treatment options based on current female breast tumors produce comparable results to female breast cancer. Increased awareness and a national registry for patients could help improve outcomes and tailor treatment recommendations to the male variant.     

A rare presentation of bilateral,synchronous male breast cancer

Rarity of male breast cancer limits available clinical research and data for management guidance and screening guidelines for patients at high risk. Here, we report on a patient with bilateral, synchronous male breast cancer with discussion of risk factors and need for possible screening.     

Hormone conditioned cancer chemotherapy for recurrent breast cancer prolongs survival

Left suprarenal-inferior mesenteric venous shunt (Inokuchi) was prescribed for 80 patients with recurrent breast cancer and the efficacy of hormone coditioned cancer chemotherapy was assessed. The patients were separated into 3 groups according to the historical regimen of combined chemotherapy: Group I; surgical hormone therapy alone, Group II; surgery plus short term chemotherapy, and Group III; surgery plus long term chemotherapy. The 5 year survival rate of the responsive patients to the surgical hormone therapy was as high as 84.6 per cent in Group III, as compared to that of Groups I and II, 41.7 per cent and 16.7, respectively. Survival was not prolonged in non-responsive patients, regardless of the group. These findings indicate that surgical hormone therapy combined with postoperative long term cancer chemotherapy is a valid and effective method for treating recurrence of breast cancer.     

Male breast cancer in patients with a familial history of breast cancer

We describe herein the clinical characteristics of five male breast carcinoma (MBC) patients with a familial history of breast carcinoma (FHBC). Four of these patients suffered from multiple primary cancers, being gastric and prostate cancer in 1, gastric cancer in 1, and asynchronous bilateral breast cancers in 2. The average age of these patients at diagnosis was not lower than that of MBC patients with no such familial history. The aggregation of cancer in these families had three prominent characteristics: (1) The families included women with early-onset breast cancers which had occurred at the ages of 38, 38, and 35 years, respectively, and/or early-onset uterine cancer which had occurred at the age of 35 years. (2) The incidence of multiple primary cancers was significantly higher in the siblings of MBC patients with a FHBC than without. (3) There were many cancers in hormone-related organs in two families.     

Male inflammatory breast cancer

We report herein the case of a 68-year-old man diagnosed with inflammatory breast cancer. The patient presented following the rapid onset of redness and swelling over the left anterior chest wall. On examination, the left chest wall and left axilla were extensively hard, and the left upper limb was swollen. Ultrasonography and computed tomography (CT) scanning disclosed a mass in the left breast, about 2 cm in diameter with an unclear margin, and swelling of the major and minor pectoral muscles. Needle biopsy of the breast mass confirmed invasive lobular carcinoma. As a radical operation was considered contraindicated, systemic and intraarterial chemotherapy using 5-fluorouracil (5-FU) and Adriamycin (ADR) were performed. Nevertheless, the patient died of carcinomatous pleurisy 6 months after the initial onset of the disease.     

早期乳腺癌行保乳手术临床分析

目的观察早期乳腺癌保乳手术的治疗效果。方法分析2000—2005年临床0～Ⅱa期女性乳腺癌患者中87例行保乳手术的疗效。采用肿瘤局部扩大切除或象限切除，以及腋淋巴结清扫，术后辅以放疗、化疗或内分泌治疗。残留腺体做阶梯状对缝，以保证乳晕部的隆起。结果保乳手术后乳房外形总满意率为93．6％，无伤口感染，无皮瓣坏死、皮下积液。随访结果局部复发率1．15％，无远处转移，无死亡病例。结论保乳手术创伤小、并发症少、恢复快、形体改变小，疗效满意，病人心理状态良好，生存质量较高。     

乳腺癌保乳手术切缘问题

尽管外科医生普遍认为保乳手术切缘应该是没有肿瘤细胞的干净切缘,而肿瘤残留将可能增加局部复发概率,甚至增加病死率;但是由于保乳手术在各个国家地区的做法不同及切缘评估方法的差异,至今无保乳手术中有关安全切缘宽度的共识或指南。保乳手术应该保证切缘无瘤,否则肿瘤的残留将使得一个根治性的手术人为转变成为姑息手术及活检手术;将随后的辅助治疗人为转变成为解救治疗。     

基层医院乳腺癌保乳手术的体会

目的探讨基层医院乳腺癌保乳手术的可行性。方法自2003年10月至2005年10月对早期乳腺癌共施行了15例保乳手术,肿瘤直径在2～3cm,手术切除肿瘤范围约2cm的正常组织以确保切缘阴性,清扫是达到腋淋巴结Ⅰ水平。结果术中冰冻病理报告所有标本各切缘无癌残留,腋淋巴结均无转移。所有病例乳房形态保持良好,患者满意。无术后切口感染、积血、积液和皮肤坏死。术后随访1～48个月,未见局部复发和远处转移。结论只要严格掌握手术指征,在基层医院施行保乳手术是可行的。     

Psychological impact and cosmetic outcome of surgical breast cancer strategies

BACKGROUND: Current surgical treatment modalities for breast cancer include breast conserving surgery, mastectomy alone and mastectomy with breast reconstruction. There are recognized benefits of breast conservation and breast reconstruction over mastectomy but there are few studies assessing this area in Australia. The aim of the present study was to compare the various surgical strategies for breast cancer treatment in terms of quality of life, cosmesis and patient satisfaction. METHODS: A chart analysis was conducted of all patients who underwent Breast Cancer Reconstruction at the Royal Adelaide Hospital Breast Unit between 1990 and 2002. Patients were then traced and asked to take part in an interview. Mastectomy and breast conservation patients who attended outpatient clinic for follow up were also approached. All three groups were interviewed and self-assessment quality of life questionnaires (Functional Assessment of Cancer Therapy-Breast, body image) were administered. The breast conservation and reconstruction groups also underwent assessment of satisfaction and cosmesis. RESULTS: A total of 78 mastectomy, 109 breast conservation and 123 breast reconstruction patients were interviewed. Quality of life assessment was similar between the three groups but the breast conservation and reconstruction patients' body image scores were superior to the mastectomy group. Patient satisfaction was higher in the reconstruction group than the breast conservation group of patients, while cosmesis was similar. CONCLUSION: While little difference was seen on quality of life assessment, body image is improved with the use of breast conservation and reconstruction. The high satisfaction and cosmesis scores in the breast reconstruction group are an indication of the superior results that can be achieved with breast reconstruction.     

Contemporary management of breast cancer during pregnancy and subsequent lactation in a multicenter cohort of young women with breast cancer

The incidence of breast cancer diagnosed during pregnancy is increasing. We sought to characterize patient, treatment, pregnancy and lactation factors among young women with newly diagnosed breast cancer during pregnancy in a prospective cohort study. We identified all women who were pregnant when diagnosed with invasive breast cancer among those enrolled in the Young Women's Breast Cancer Study (NCT01468246), and collected details on pregnancy, birth and lactation from surveys, and treatment information medical record review. Of 1302 enrolled participants, 976 women with invasive breast cancer completed full baseline surveys, among whom 39 (4.0%) patients reported being pregnant at diagnosis. Median age at diagnosis was 34 years (range: 25‐40), with stage distribution: I, 28%; II, 44%; III, 23%; and IV, 5%. 74% of patients (29/39) had grade 3 tumors, 59% (23/39) ER‐positive, and 31% (12/39) HER2‐positive disease. 23 (59%) had surgery during pregnancy, 4 (17%) during the first trimester. Among the women who had surgery during pregnancy, 61% (14/23) underwent lumpectomy, 35% (8/23) unilateral, and 4% (1/23) bilateral mastectomy. All patients who had chemotherapy (51%, 20/39) received it in second and third trimesters, and had ACx4. There were 31 live births, 2 spontaneous, and 5 therapeutic abortions. Among live births, 16 (41%) were before 37 weeks of gestation. Three women reported breastfeeding. Within 6 months after delivery, comprehensive staging in 13 patients showed upstaging in four patients. In a contemporary cohort of young women with breast cancer, pregnancy at diagnosis is relatively uncommon. Treatment during pregnancy can generally be consistent with standard surgical and chemotherapy approaches, with attention to timing of therapies. Longer‐term outcomes including effects of some timing issues including delayed use of anti‐HER2 therapy on patient outcomes warrant further research.