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1.  miR-127 Regulates Cell Proliferation and Senescence by Targeting BCL6 
PLoS ONE  2013;8(11):e80266.
Cellular senescence occurs as a response to extracellular and intracellular stresses and contributes to aging and age-related pathologies. Emerging evidence suggests that cellular senescence also acts as a potent tumor suppression mechanism that prevents the oncogenic transformation of primary human cells. Recent reports have indicated that miRNAsact as key modulators of cellular senescence by targeting critical regulators of the senescence pathways. We previously reported that miR-127 is up-regulated in senescent fibroblasts. In this report, we identified miR-127 as a novel regulator of cellular senescence that directly targets BCL6. We further showed that miR-127 is down-regulated in breast cancer tissuesand that this down-regulation is associated with up-regulation of BCL6. Over-expression of miR-127 or depletion of BCL6 inhibits breast cancer cell proliferation. Our data suggest that miR-127 may function as a tumor suppressor that modulates the oncogene BCL6.
doi:10.1371/journal.pone.0080266
PMCID: PMC3840165  PMID: 24282530
2.  Value of pre-treatment biomarkers in prediction of response to neoadjuvant endocrine therapy for hormone receptor-positive postmenopausal breast cancer 
Objective
To determine the predictive ability of biomarkers for responses to neoadjuvant endocrine therapy (NET) in postmenopausal breast cancer.
Methods
Consecutive 160 postmenopausal women with T1-3N0-1M0 hormone receptor (HR)-positive invasive breast cancer were treated with anastrozole for 16 weeks before surgery. New slides of tumor specimens taken before and after treatment were conducted centrally for biomarker analysis and classified using the Applied Imaging Ariol MB-8 system. The pathological response was evaluated using the Miller & Payne classification. The cell cycle response was classified according to the change in the Ki67 index after treatment. Multivariable logistic regression analysis was used to calculate the combined index of the biomarkers. Receiver operating characteristic (ROC) curves were used to determine whether parameters may predict response.
Results
The correlation between the pathological and cell cycle responses was low (Spearman correlation coefficient =0.241, P<0.001; Kappa value =0.119, P=0.032). The cell cycle response was significantly associated with pre-treatment estrogen receptor (ER) status (P=0.001), progesterone receptor (PgR) status (P<0.001), human epidermal growth factor receptor 2 (Her-2) status (P=0.050) and the Ki67 index (P<0.001), but the pathological response was not correlated with these factors. Pre-treatment ER levels [area under the curve (AUC) =0.634, 95% confidence interval (95% CI), 0.534-0.735, P=0.008] and combined index of pre-treatment ER and PgR levels (AUC =0.684, 95% CI, 0.591-0.776, P<0.001) could not predict the cell cycle response, but combined index including per-treatment ER/PR/Her-2/Ki67 expression levels could (AUC =0.830, 95% CI, 0.759-0.902, P<0.001).
Conclusions
The combined use of pre-treatment ER/PgR/Her-2/Ki67 expression levels, instead of HR expression levels, may predict the cell cycle response to NET.
doi:10.3978/j.issn.1000-9604.2013.08.01
PMCID: PMC3752359  PMID: 23997526
Breast cancer; neoadjuvant endocrine therapy (NET); responsiveness; predictive value
3.  Protein phosphatase PP6 is required for homology-directed repair of DNA double-strand breaks 
Cell Cycle  2011;10(9):1411-1419.
DNA double-strand breaks (DSBs) are among the most lethal lesions associated with genome stability, which, when destabilized, predisposes organs to cancers. DSBs are primarily fixed either with little fidelity by non-homologous end joining (NHEJ) repair or with high fidelity by homology-directed repair (HDR). The phosphorylated form of H2AX on serine 139 (γ-H2AX) is a marker of DSBs. In this study, we explored if the protein phosphatase PP6 is involved in DSB repair by depletion of its expression in human cancer cell lines, and determined PP6 expression in human breast cancer tissues by immunohistochemistry staining. We found that bacterially produced PP6c (the catalytic subunit of PP6)-containing heterotrimeric combinations exhibit phosphatase activity against γ-H2AX in the in vitro phosphatase assays. Depletion of PP6c or PP6R2 led to persistent high levels of γ-H2AX after DNA damage and a defective HDR. Chromatin immunoprecipitation assays demonstrated that PP6c was recruited to the region adjacent to the DSB sites. Expression of PP6c, PP6R2 and PP6R3 in human breast tumors was significantly lower than those in benign breast diseases. Taken together, our results suggest that γ-H2AX is a physiological substrate of PP6 and PP6 is required for HDR and its expression may harbor a protective role during the development of breast cancer.
doi:10.4161/cc.10.9.15479
PMCID: PMC3117043  PMID: 21451261
protein phosphatase; PP6; γ-H2AX; DNA double-strand break; homology-directed repair
4.  Expression of ER-α36, a Novel Variant of Estrogen Receptor α, and Resistance to Tamoxifen Treatment in Breast Cancer 
Journal of Clinical Oncology  2009;27(21):3423-3429.
Purpose
Recently, a 36-kDa variant of estrogen receptor α (ER-α66), ER-α36, has been identified and cloned. ER-α36 predominantly localizes on the plasma membrane and in the cytoplasm and mediates a membrane-initiated “nongenomic” signaling pathway. Here, we investigate the association between ER-α36 expression and tamoxifen resistance in patients with breast cancer.
Patients and Methods
ER-α36 protein expression in tumors from 896 women (two independent cohorts, 1 and 2) with operable primary breast cancer was assessed using an immunohistochemistry assay.
Results
In the first cohort of 710 consecutive patients, overexpression of ER-α36 was associated with poorer disease-free survival (DFS) and disease-specific survival (DSS) in patients with ER-α66–positive tumors who received tamoxifen treatment (chemotherapy plus tamoxifen or tamoxifen alone, n = 307). In contrast, ER-α36 was not associated with survival in patients with ER-α66–positive tumors who did not receive tamoxifen (chemotherapy alone, n = 129) and in patients with ER-α66–negative tumors whether they received tamoxifen (n = 73) or not (n = 149). In the second cohort of 186 patients who only received tamoxifen as adjuvant therapy, overexpression of ER-α36 was significantly associated with poorer DFS and DSS in 156 ER-α66–positive patients from this cohort, and ER-α36 remained an independent unfavorable factor for both DFS and DSS in these 156 patients by a multivariate analysis (DFS: hazard ratio [HR] = 5.47; 95% CI, 1.81 to 16.51; P =. 003; DSS: HR = 13.97; 95% CI, 1.58 to 123.53; P = .018).
Conclusion
Women with ER-α66–positive tumors that also express high levels of ER-α36 are less likely to benefit from tamoxifen treatment.
doi:10.1200/JCO.2008.17.2254
PMCID: PMC2717750  PMID: 19487384

Results 1-4 (4)