IKKα inhibition re-sensitizes acquired adriamycin-resistant triple negative breast cancer cells to chemotherapy-induced apoptosis.

IKKα has been shown to be responsible of multiple pro-tumorigenic functions and therapy resistance independent of canonical NF-κB, but its role in acquired chemotherapy resistance in breast cancer remains unclarified. In this study, we obtained pre-treatment biopsy and post-treatment mastectomy specimens from a retrospective cohort of triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy(NAC) (n = 43). Immunohistochemical methods were used to detect the expression of IKKα before and after NAC, and the relationship between IKKα and the pathologic response to NAC was examined. In addition, we developed a new ADR-resistant MDA-MB-231 cell line(MDA-MB-231/ADR) and analyzed these cells for changes in IKKα expression, the role and mechanisms of the increased IKKα in promoting drug resistance were determined in vitro and in vivo. We demonstrated that the expression of IKKα in residual TNBC tissues after chemotherapy was significantly higher than that before chemotherapy, and was positively correlated with lower pathological reaction. IKKα expression was significantly higher in ADR-resistant TNBC cells than in ADR-sensitive cells, IKKα knockdown results in apoptotic cell death of chemoresistant cells upon drug treatment. Moreover, IKKα knockdown promotes chemotherapeutic drug-induced tumor cell death in an transplanted tumor mouse model. Functionally, we demonstrated that IKKα knockdown significantly upregulated the expression of cleaved caspase 3 and Bax and inhibited the expression of Bcl-2 upon ADR treatment. Our findings highlighted that IKKα exerts an important and previously unknown role in promoting chemoresistance in TNBC, combining IKKα inhibition with chemotherapy may be an effective strategy to improve treatment outcome in chemoresistant TNBC patients.

Efficacy of Iodine-125 Seed Implantation in Locoregionally Recurrent and Unresectable Breast Cancer: a Retrospective Study.

The management of locoregionally recurrent and unresectable breast cancer is a therapeutic challenge. This retrospective study aimed to assess the efficacy of 125I seed implantation brachytherapy as a palliative management in locoregionally recurrent breast cancer. We analyzed 36 locoregionally recurrent and unresectable breast cancers in our hospital between 2012 and 2016. All patients were treated with CT-guided 125I seed permanent implantation. The dose distribution of 125I seeds was calculated using a computerized treatment planning system. Complete response, partial response, stable disease, and local tumor control rates were calculated. Long-term efficacy was assessed based on survival rates ranging from 1 to 4 years. The follow-up period ranged from 6 to 53 months. The median local control was 28 months (95% CI: 16.2-39.8 months). The percentage of patients who showed 6-month, 1-year, 2-year, and 3-year local control was 97.2%, 77.8%, 52.8%, and 33.3%, respectively. Median survival time for all patients was 48 months (95% CI: 40.9-55.1 months); 1-year, 2-year, 3-year, and 4-year survival rates were 97.2%, 80.6%, 63.9%, and 46.5%, respectively. Pain relief response rate was 88.9%. No serious complications were detected during the follow-up period. The results of this study demonstrate that 125I seed implantation could be considered a feasible and promising minimally invasive therapy for locoregionally recurrent and unresectable breast carcinoma.

[Effects of FBI-1 silencing on proliferation and apoptosis of triple-negative breast cancer cell line MDA-MB-231].

This work aimed to observe the effects of short hairpin RNA (shRNA)-silenced FBI-1 (factor that binds to the inducer of short transcripts of human immunodeficiency virus-1) on proliferation and apoptosis of triple-negative breast cancer cell line MDA-MB-231. qRT-PCR and Western blot analysis were applied to detect the mRNA and/or protein expression of FBI-1, Bcl-2, Bax, cleaved-Caspase 3 and Survivin. RNA interference method was used to silence FBI-1 expression in MDA-MB-231 cells. CCK-8 and colony formation assay were employed to detect the cell proliferation. Flow cytometry was employed for examining cell apoptosis. In vivo tumorigenicity of MDA-MB-231 cells was detected by tumor transplantation in nude mice. The results showed that the mRNA and protein expressions of FBI-1 were higher in MDA-MB-231 cells compared with those in normal human mammary epithelial cells MCF-10A. FBI-1 gene silencing inhibited proliferation and induced apoptosis of MDA-MB-231 cells in vitro, together with decreased Bcl-2 and Survivin protein expression, increased Bax protein expression and activated Caspase 3. Moreover, FBI-1 gene silencing inhibited the tumorigenesis of MDA-MB-231 cells in vivo. These results suggest that silencing of FBI-1 gene inhibits proliferation, induces apoptosis and suppresses the tumorigenesis of MDA-MB-231 cells.

Expression of CDKN1A/p21 and TGFBR2 in breast cancer and their prognostic significance.

BACKGROUND: A new diagnostic and prognostic biomarker may be of value in cancer diseases. Our study aimed to evaluate the CDKN1A/p21 and TGFBR2 level measurable in a cohort of patients with breast cancer after mastectomy, and to confirm their suitability to serve as prognostic biomarkers of the cancer. METHODS: The expression levels of CDKN1A/p21 and TGFBR2 were detected by reverse transcription-PCR (RT-PCR), western blot assay and immunohistochemical staining for 65 primary tumor samples and paired adjacent noncancerous breast tissues. Their relations to clinicopathologic parameters and to the prognosis of patients with breast cancer were analyzed. RESULTS: We found the mRNA and protein expression levels of CDKN1A/p21 were significantly upregulated in breast cancer tissues compared with adjacent nontumorous breast tissues. Increased CDKN1A/p21 expression showed a significant correlation with larger tumor size (P=0.014), higher tumor dedifferentiation grade (P=0.021), lymph node metastasis (P=0.019) and a shorter disease-free survival (P=0.044). Contrarily, the expression levels of TGFBR2 mRNA and protein were significantly decreased in breast cancer tissues compared with adjacent nontumorous breast tissues. Underexpression of TGFBR2 in breast cancer was correlated with larger tumor size (P=0.034), lymph node metastasis (P=0.039) and a shorter disease-free survival (P=0.035). Statistical analysis suggested that there was no significant association between CDKN1A/p21 and TGFBR2 expression. CONCLUSIONS: in summary, our results suggested that high CDKN1A/p21 and low TGFBR2 expression was closely correlated with adverse pathological parameters and poor prognosis in breast cancer. Both CDKN1A/p21 and TGFBR2 are presented as possible candidates for breast cancer biomarkers.

Prognostic value of Ki67 expression in HR-negative breast cancer before and after neoadjuvant chemotherapy.

BACKGROUND: Immunohistochemical (IHC) expression of Ki67 has been identified as a prognostic and predictive marker in hormone receptor (HR)-positive breast cancer, however, there is little evidence of the association of Ki67 with prognosis in HR-negative patients. We aimed to assess the benefit of Ki67 assessment in HR-negative breast cancers after neoadjuvant chemotherapy (NAC). METHODS: In the present study, a total of 183 HR-negative breast cancer patients with Stage II to III that treated with anthracycline and/or taxane-based neoadjuvant chemotherapy between 2004 and 2011 were retrospectively analyzed. Endocrine therapy and trastuzumab was not administered to any patients in this study. Clinical and pathological features of the patients with breast cancer were retrieved from the hospital records. Predictive factors for NAC response and survival were analyzed. RESULTS: Of the 183 patients, 122 (66.6%) were HR- HER2+, and 61 (33.3%) were triple-negative. The clinical response rates were similar across breast cancer subtype. Patients whose tumors contained high Ki67 expression effectively responded to NAC. Ki67 labeling index was a predictive marker for pathologic complete response (pCR). Ki67 expression showed a positive correlation with HER2 status, tumor size, lymph node status, lymphovascular invasion and tumor grade. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free survival (DFS), but no correlation of Ki-67 expression with overall survival (OS) was observed. CONCLUSIONS: Our results suggest that Ki67 expression in HR-negative breast cancer may improve the assessment of pathological response after NAC, and Ki67 score in residual tumor was an independent prognosticator for DFS in the HR-negative breast cancer patients.

Prognostic value of hormone receptor status conversion following neoadjuvant chemotherapy in a series of operable breast cancer patients.

BACKGROUND: To investigate the prognostic value of hormone receptor (HR) status conversion after neoadjuvant chemotherapy (NAC) in patients with primary breast cancer. METHODS: 267 stage II-III breast cancer patients treated with NAC who had residual disease in the breast after NAC were retrospectively studied. The patients were divided into four groups based on the HR status: Group A, patients with HR-positive both before and after NAC; Group B, patients with HR status positive-to-negative change; Group C, patients with HR status negative-to-positive change; Group D, patients with HR-negative both before and after NAC. Patients with positive HR status (regardless of before or after NAC) were treated with adjuvant endocrine therapy, and a survival analysis was performed. RESULTS: In total, 15.7% of patients had HR status change after NAC. progression-free survival (PFS) in Group A was similar to that in Group C (hazard ratio, 1.16; P = 0.652), but that in Group B was significantly lesser than that in Group A (hazard ratio, 6.88; P = 0.001), and that in Group C was significantly longer than that in Group D (hazard ratio, 6.88; P = 0.001). A similar pattern of results was obtained for overall survival (OS). CONCLUSIONS: The switch of HR status after NAC is remarkable for breast cancer. An HR switch may identify patients who would benefit from adjuvant endocrine therapy and impact the long-term outcome.

Sorafenib-based therapy in HER2-negative advanced breast cancer: Results from a retrospective pooled analysis of randomized controlled trials.

A standard systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) is yet to be identified. Sorafenib has been developed for the treatment of solid tumors, including breast cancer, as an oral multikinase inhibitor with antiangiogenic and antiproliferative activity. The aim of the present study was to assess the efficacy and safety of sorafenib in patients with HER2-negative ABC by performing a meta-analysis. A literature search was applied to databases, including PubMed, EMBASE, the Cochrane Library Databases, American Society of Clinical Oncology and the European Society for Medical Oncology, with the search terms 'advanced breast cancer' and 'sorafenib' and relevant studies were selected for analysis. The data extracted from the selected studies included progression-free survival (PFS), time to progression (TTP), overall survival (OS) and overall response rate (ORR). Major adverse events (AEs) were also analyzed. A total of four randomized controlled trials containing 844 cases were identified. Combined results revealed that when compared with chemotherapy (or with anti-hormone receptor therapy) alone, sorafenib-based therapy significantly increased the PFS [hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.54-1.02] and TTP (HR, 0.74; 95% CI, 0.50-0.97), but not the OS (HR, 0.95; 95% CI, 0.75-1.15) and ORR (relative risk, 1.19; 95% CI, 1.01-1.39). In addition, the incidence of grade 3/4 AEs, including hand-foot skin syndrome, anemia, fatigue, rash and stomatitis, were significantly increased in patients that received sorafenib-based therapy. Therefore, the results from the current meta-analysis indicated that sorafenib-based therapy improved the PFS and TTP in patients with HER2-negative ABC, but not the OS and ORR. In addition, combination treatment was associated with increased toxicities and frequently required dose reductions.

Radiobiological effect induced by different activities of (125)I seed brachytherapy in a hepatocellular carcinoma model.

BACKGROUND: Iodine 125 ((125)I) seed irradiation is an effective non-surgical treatment for unresectable hepatocellular carcinoma (HCC) patients. However, the safety and tolerability of (125)I seed sequential irradiation therapy remain unclear, there is no unified standard of brachytherapy radiation dose, and further study on the basic radiobiology of continuous rate irradiation is necessary. METHODS: Forty Kunming-mice (KM-mice, China) were injected with suspensions of human hepatocellular carcinoma cells (H22) to create an animal model and mimic (125)I seed implantation. The survival rates of mice, curative effect, pathological impairments including apoptosis and necrosis were investigated. The mice were randomly divided into four groups, A, B, C and D. In group A, 0.78 mCi (125)I seeds were implanted into the tumor focus. In groups B and C, 0.58 mCi and 0.38 mCi (125)I seeds were inserted at the same location, respectively. Group D was a control group, without any treatment. After 28 days of therapy, the survival rates and the tumor size were measured, and pathological impairments was measured by light or electron microscopy. RESULTS: The tumor volume inhibition rate was 68.21% ± 3.21%, 51.38% ± 4.96%, and 35.71% ± 2.79% after 0.78 mCi, 0.58 mCi, and 0.38 mCi (125)I seeds irradiation, respectively. However, radiation-related side effects were also observed in the high-dose group. Pathological results showed that radiation effect was closely associated with radiation dose, as the increase of radiation dose, an increase in apoptosis and necrosis was detected. Significant cellular impairments were noted by pathological analysis under electron microscopy. CONCLUSIONS: Our results demonstrate that the Kunming-mouse is an ideal animal to study (125)I brachytherapy, and the curative effect was closely associated with radiation dose. High-dose of brachytherapy may effectively increase apoptosis and necrosis in liver cells in KM-mice. A dose of 0.58 mCi (125)I radioactive particles may be a safe, effective and minimally invasive therapeutic option for liver cancer.

Platinum-based chemotherapy in triple-negative breast cancer: A meta-analysis.

Triple-negative breast cancer (TNBC) tumors do not express estrogen, progesterone or HER2/neu-receptors. There are no specific treatment guidelines for TNBC patients, however, it has been postulated that their phenotypic and molecular similarity to BRCA1-associated cancers would confer sensitivity to certain cytotoxic agents, including platinum. The aim of this meta-analysis was to evaluate the clinical outcome of breast cancer patients treated with platinum-based chemotherapy who had TNBC compared with those with non-TNBC. Electronic (MEDLINE, EMBASE and Cochrane Library databases) and manual searches were conducted throughout December 2011 to identify trials evaluating the use of platinum-based chemotherapy for patients with breast cancer. The methodological quality was assessed in accordance with the QUOROM statement. Seven studies met the eligibility criteria, with a total of 717 patients. Of these patients, 225 were TNBC patients (31%), 492 were non-TNBC patients (69%), 275 received platinum-based neo-adjuvant chemotherapy and 442 had advanced/metastatic breast cancers. The results showed that during neo-adjuvant chemotherapy, the clinical complete response (cCR) rate and the pathological complete response (pCR) rates were significantly higher for the TNBC group compared with the non-TNBC group (OR, 2.68; 95% CI, 1.69-6.57; P=0.03 and OR, 2.89; 95% CI, 1.28, 6.53; P= 0.01, respectively). However, in advanced/metastatic breast cancers, the cCR, partial response (PR) and the disease control rates for the TNBC group were not significantly different compared with the non-TNBC group. The 6-month progression-free survival (PFS) rate for the TNBC group was higher than that of the non-TNBC group in all patients (OR, 1.81; 95% CI, 1.11-2.96; P= 0.02). However, the 1- and 2-year PFS rates were not significantly different (OR, 1.42; 95% CI, 0.69-2.92; P=0.35 and OR, 1.11; 95% CI, 0.35-3.52; P= 0.85, respectively). Furthermore, the PFS rates were not significantly different between the groups in patients with advanced/metastatic breast cancer. In conclusion, platinum-based chemotherapy in the breast cancer patients with TNBC showed an improved short-term efficacy compared with the non-TNBC group during neo-adjuvant chemotherapy, but has not yet been demonstrated to have an improved effect in advanced breast cancer.