MiR-526b-3p Attenuates Breast Cancer Stem Cell Properties and Chemoresistance by Targeting HIF-2α/Notch Signaling

Chemoresistance is a severe clinical challenge in breast cancer. Hypoxia and cancer stem cells (CSCs) contribute to the paclitaxel (PTX) resistance, but the molecular mechanisms are still elusive. MicorRNAs (miRNA) have been considered a promising therapeutic strategy in various cancers. Here, we identified the crucial function of miR-526b-3p in regulating PTX resistance and CSC properties. Our data demonstrated that miR-526b-3p mimic repressed the cell viability of breast cancer cells. The counts of Edu-positive cells were reduced by miR-526b-3p in breast cancer cells. Meanwhile, the apoptosis of breast cancer cells was induced by miR-526b-3p. Tumorigenicity analysis in the nude mice confirmed that miR-526b-3p attenuated the breast cancer cell growth in vivo. Significantly, hypoxia could enhance IC50 value of PTX in breast cancer cells. IC50 value of PTX was induced in breast cancer mammospheres. The hypoxia-inducible factor 2α (HIF-2α) expression was enhanced, but miR-526b-3p expression was repressed under hypoxia in breast cancer cells. Also, breast cancer mammospheres presented high HIF-2α expression and low miR-526b-3p expression. The inhibition of miR-526b-3p enhanced the IC50 value of PTX in breast cancer cells. MiR-526b-3p inhibitor enhanced the colony formation counts of PTX-treated breast cancer cells. The treatment of miR-526b-3p mimic suppressed the sphere formation counts of breast cancer cells and inhibited ALDH1 and Nanog expression. MiR-526b-3p was able to target HIF-2α in the cells. The overexpression enhanced but miR-526b-3p reduced the IC50 value of PTX in breast cancer cells, in which the overexpression of HIF-2α could rescue the miR-526b-3p-inhibited IC50 value of PTX. Overexpression of HIF-2α reversed miR-526b-3p-regulated apoptosis, colony formation ability, and ALDH1 and Nanog expression in the cells. Interestingly, the overexpression of HIF-2α induced but miR-526b-3p repressed the expression of HIF-2α, Hey2, and Notch in PTX-treated breast cancer cells, while HIF-2α could reverse the effect of miR-526b-3p. In conclusion, miR-526b-3p attenuated breast cancer stem cell properties and chemoresistance by targeting HIF-2α/Notch signaling. MiR-526b-3p may be utilized in the relieving chemoresistance in breast cancer.

Survival With Surgery Is Superior to Survival Without Surgery in Breast Cancer Patients Aged 85 years or Older: A Retrospective Study

Background Surgical treatment of breast cancer patients aged 85 years or older is still controversial. Methods A series of surgically treated breast cancer patients aged 85 years or older was evaluated. The clinicopathological features and outcomes of these patients were compared with the features and outcomes of breast cancer patients in the same age group who were managed without surgery. Results A total of 45 patients (75%) received surgical treatment, and 15 patients (25%) were managed without surgery. Significantly more patients treated by surgery underwent systemic treatment than patients managed without surgery ( P = .003). The 5-year disease-free survival rate of patients treated by surgery was 80.7% (95% confidence interval: 66.2–98.5%), which was significantly higher than that of the patients managed without surgery ( P = .001). Conclusions The surgical treatment of breast cancer patients aged 85 years or older is warranted. This outcome was achieved with the use of hormonal therapy.

TFEB, SIRT1, CARM1, Beclin-1 expression and PITX2 methylation in breast cancer chemoresistance: a retrospective study

Background Breast cancer chemoresistance is attributed to a wide variety of mechanisms, including autophagy. Transcription factor EB (TFEB) has been recently identified and characterized as one major regulator of autophagy and lysosomal genesis. Objective This study aims to evaluate the prognostic impact of TFEB and its pathway in breast cancer chemoresistance. Methods This retrospective study analyzes the expression of TFEB, CARM1, SIRT1, and Beclin-1 and the methylation of PITX2 in breast carcinoma. A group of breast cancer patients treated with chemotherapy, who relapsed within 12 months from treatment initiation, were compared to a sub-cohort of chemo-treated patients who did not recur within 12 months of follow-up. The expression of TFEB, CARM1, SIRT1, and Belcin-1 was analyzed using immunohistochemistry or RT-PCR on formalin-fixed paraffin-embedded samples. PITX2 methylation was tested with the diagnostic CE-marked kit Therascreen PITX2 RGQ PCR. In the final model, 136 cases of chemo-treated breast cancer were included. Results A higher TFEB and Beclin-1 expression correlate with shorter survival in patients with chemo-treated invasive breast cancer (respectively HR 3.46, CI.95 1.27–9.47, p < 0.05 and 7.11, CI.95 2.54–19.9). TFEB, CARM1, and SIRT1 are positively correlated with Beclin-1. The protein expression of SIRT1 is significantly associated with TFEB and CARM1 so that a very low SIRT1 expression (lower than the first quartile of the H-score distribution) correlates with a low expression of TFEB and CARM1 and with longer survival. SIRT1 seems to have a lower H-score in the basal-like and HER2-enriched tumors than the luminal subtypes. Beclin-1 and TFEB seem to have a higher H-score in the basal-like and HER2-enriched tumors than the luminal subtypes. PITX2 methylation analysis was feasible only in 65% of the selected samples, but no significant differences between cases and controls were found, and there was also no correlation with the expression of the TFEB pathway. Conclusions TFEB, SIRT1, and Beclin-1 seem to have a potential prognostic significance in patients with chemo-treated breast cancer, likely because of their role in the regulation of autophagy. In addition, no correlation between TFEB and PITX2 methylation was found, likely because they perform two different roles within the autophagy process.

Evaluation of the Effect of Combination Chemotherapy with Five-day Infusion of Fluorouracil Plus Vinorelbine in Pretreated Metastatic Breast Cancer Patients

Background continuous infusion (CI) of 5-fluorouracil (5-FU) has proven in several studies to be an active and well tolerated treatment for advanced pretreated breast cancer. Navelbine has also shown activity in this setting. Aim This is retrospective study to evaluate the clinical activity and side effects of a combination chemotherapy consisting of a five-day continuous infusion of fluorouracil and i.v. vinorelbine in metastatic previously treated breast cancer patients. Patients and Methods Fifty-four patients received 5FU 600 mg/m2/d for 5 consecutive days as a continuous infusion and vinorelbine 25 mg/m2 on days 1 and 5 as a short intravenous (I/V) infusion every 3 weeks. Results Eleven (20.4%) complete responses, 20 (37%) partial responses and 14 (25.9%) stationary disease were documented, accounting for a clinical benefit rate of 83.3%. The median progression free survival was 6.8 months. The median overall survival was 25.8 months. Treatment was well tolerated, with Grade 3 anemia, febrile neutrobenia and stomatitis in 9.3%, 5.6% and 1.9% respectively as the main toxic reactions. Conclusions: This drug combination is active in metastatic previously treated breast cancer patients with acceptable toxicity profile.

SAR Performance of Rectangular Microstrip Antenna for Breast Cancer Hyperthermia Treatment with Different Period of Treatment Procedure

Cancer treatment using hyperthermia techniques recently become the interest among researchers in investigating and improving certain deficiencies of the treatment since this treatment has the potential to denaturate cancer into necrotic tissue. Hyperthermia uses high heat from 41°C to 45°C at a certain period of time. It is difficult to control the focus position distance of heat distribution on the treated tissue. Therefore, this paper presents the rectangular microstrip as hyperthermia applicator, which deliver the heat on the targeted treated breast cancer tissue with different period of time in order to obtain sufficient heat or SAR distribution. Sim4LifeLight software simulator is used to design, simulate and generate the specific absorption rate (SAR) distribution on the treated tissue. Three frequencies of 434MHz, 915MHz and 2450MHz are used to be compared. Based on the results, 2450MHz shows better performance than the other two frequencies. However, there is a certain limitation, such as skin burn and unwanted hotspots, that need to be further improved. The cancer is sufficiently heating at different operating frequencies at different periods of procedures.

Impact of systemic adjuvant therapy and CYP2D6 activity on mammographic density in a cohort of tamoxifen-treated breast cancer patients

Purpose Change in mammographic density has been suggested to be a proxy of tamoxifen response. We investigated the effect of additional adjuvant systemic therapy and CYP2D6 activity on MD change in a cohort of tamoxifen-treated pre- and postmenopausal breast cancer patients. Methods Swedish breast cancer patients (n = 699) operated 2006–2014, genotyped for CYP2D6, having at least three months postoperative tamoxifen treatment, a baseline, and at least one follow-up digital mammogram were included in the study. Other systemic adjuvant treatment included chemotherapy, goserelin, and aromatase inhibitors. Change in MD, dense area, was assessed using the automated STRATUS method. Patients were stratified on baseline characteristics, treatments, and CYP2D6 activity (poor, intermediate, extensive, and ultrarapid). Relative density change was calculated at year 1, 2, and 5 during follow-up in relation to treatments and CYP2D6 activity. Results Mean relative DA decreased under the follow-up period, with a more pronounced MD reduction in premenopausal patients. No significant effect of chemotherapy, aromatase inhibitors, goserelin, or CYP2D6 activity on DA change was found. DA did not revert to baseline levels after tamoxifen discontinuation. Conclusion Our results indicate that other systemic adjuvant therapy does not further reduce MD in tamoxifen-treated breast cancer patients. We could not confirm the previously suggested association between CYP2D6 activity and MD reduction in a clinical setting with multimodality adjuvant treatment. No rebound effect on MD decline after tamoxifen discontinuation was evident.

MiR-9-3p regulates the biological functions and drug resistance of gemcitabine-treated breast cancer cells and affects tumor growth through targeting MTDH

This study explored the role of MTDH in regulating the sensitivity of breast cancer cell lines to gemcitabine (Gem) and the potential miRNAs targeting MTDH. The expression of MTDH in cancer tissues and cells was detected by immunohistochemical staining or qRT-PCR. The target genes for MTDH were predicted by bioinformatics and further confirmed by dual-luciferase reporter assay and qRT-PCR. Cancer cells were transfected with siMTDH, MTDH, miR-9-3p inhibitor, or mimics and treated by Gem, then CCK-8, colony formation assay, tube formation assay, flow cytometry, wound healing assay, and Transwell were performed to explore the effects of MTDH, miR-9-3p, and Gem on cancer cell growth, apoptosis, migration, and invasion. Expressions of VEGF, p53, cleaved caspase-3, MMP-2, MMP-9, E-Cadherin, N-Cadherin, and Vimentin were determined by Western blot. MTDH was high-expressed in cancer tissues and cells, and the cells with high-expressed MTDH were less sensitive to Gem, while silencing MTDH expression significantly promoted the effect of Gem on inducing apoptosis, inhibiting cell migration, invasion, and growth, and on regulating protein expressions of cancer cells. Moreover, miR-9-3p had a targeted binding relationship with MTDH, and overexpressed miR-9-3p greatly promoted the toxic effects of Gem on cancer cells and expressions of apoptosis-related proteins, whereas overexpressed MTDH partially reversed such effects of overexpressed miR-9-3p. The study proved that miR-9-3p regulates biological functions, drug resistance, and the growth of Gem-treated breast cancer cells through targeting MTDH.

Survival with Surgery is Superior to Survival Without Surgery in Breast Cancer Patients Aged 85 Years or Older: A Retrospective Study

Background: Surgical treatment of breast cancer patients aged 85 years or older is still controversial. Methods: A series of surgically treated breast cancer patients aged 85 years or older was evaluated. The clinicopathological features and outcomes of these patients were compared with the features and outcomes of breast cancer patients in the same age group who were managed without surgery. Results: A total of 45 patients (75%) received surgical treatment, and 15 patients (25%) were managed without surgery. The differences between ages, tumor status, nodal status, stage and immunopathological status of the patients undergoing and not undergoing surgery were not significant. Significantly more patients treated by surgery underwent systemic treatment than patients managed without surgery (P=0.004). The three-year disease-free survival rate of patients treated by surgery was higher than that of the patients managed without surgery (90.6% vs 67.5%, respectively; P<0.001).Conclusions: The surgical treatment of breast cancer patients aged 85 years or older is warranted. This outcome was achieved with the use of hormonal therapy.