Browsing by Subject "Triple Negative Breast Neoplasms"

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    Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer
    (Springer Nature, 2019-04) Xu, Jiangsheng; Liu, Yunhua; Li, Yujing; Wang, Hai; Stewart, Samantha; Van der Jeught, Kevin; Agarwal, Pranay; Zhang, Yuntian; Liu, Sheng; Zhao, Gang; Wan, Jun; Lu, Xiongbin; He, Xiaoming; Medical and Molecular Genetics, School of Medicine
    TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in silico analysis, we identified POLR2A in the TP53-neighbouring region as a collateral vulnerability target in TNBC tumours, suggesting that its inhibition via small interfering RNA (siRNA) may be an amenable approach for TNBC targeted treatment. To enhance bioavailability and improve endo/lysosomal escape of siRNA, we designed pH-activated nanoparticles for augmented cytosolic delivery of POLR2A siRNA (siPol2). Suppression of POLR2A expression with the siPol2-laden nanoparticles leads to enhanced growth reduction of tumours characterized by hemizygous POLR2A loss. These results demonstrate the potential of the pH-responsive nanoparticle and the precise POLR2A targeted therapy in TNBC harbouring the common TP53 genomic alteration.
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    PSIP1/p75 promotes tumorigenicity in breast cancer cells by promoting the transcription of cell cycle genes
    (Oxford University Press, 2017-10-01) Singh, Deepak K.; Gholamalamdari, Omid; Jadaliha, Mahdieh; Li, Xiao Ling; Lin, Yo-Chuen; Zhang, Yang; Guang, Shuomeng; Hashemikhabir, Seyedsasan; Tiwari, Saumya; Zhu, Yuelin J.; Khan, Abid; Thomas, Anu; Chakraborty, Arindam; Macias, Virgilia; Balla, Andre K.; Bhargava, Rohit; Janga, Sarath Chandra; Ma, Jian; Prasanth, Supriya G.; Lal, Ashish; Prasanth, Kannanganattu V.; BioHealth Informatics, School of Informatics and Computing
    Breast cancer (BC) is a highly heterogeneous disease, both at the pathological and molecular level, and several chromatin-associated proteins play crucial roles in BC initiation and progression. Here, we demonstrate the role of PSIP1 (PC4 and SF2 interacting protein)/p75 (LEDGF) in BC progression. PSIP1/p75, previously identified as a chromatin-adaptor protein, is found to be upregulated in basal-like/triple negative breast cancer (TNBC) patient samples and cell lines. Immunohistochemistry in tissue arrays showed elevated levels of PSIP1 in metastatic invasive ductal carcinoma. Survival data analyses revealed that the levels of PSIP1 showed a negative association with TNBC patient survival. Depletion of PSIP1/p75 significantly reduced the tumorigenicity and metastatic properties of TNBC cell lines while its over-expression promoted tumorigenicity. Further, gene expression studies revealed that PSIP1 regulates the expression of genes controlling cell-cycle progression, cell migration and invasion. Finally, by interacting with RNA polymerase II, PSIP1/p75 facilitates the association of RNA pol II to the promoter of cell cycle genes and thereby regulates their transcription. Our findings demonstrate an important role of PSIP1/p75 in TNBC tumorigenicity by promoting the expression of genes that control the cell cycle and tumor metastasis.
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    β-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells
    (PLoS, 2015-02-06) Xu, Jinhua; Prosperi, Jenifer R.; Choudhury, Noura; Olopade, Olufunmilayo I.; Goss, Kathleen H.; Department of Biochemistry and Molecular Biology, IU School of Medicine
    Our previous data illustrated that activation of the canonical Wnt signaling pathway was enriched in triple-negative breast cancer and associated with reduced overall survival in all patients. To determine whether Wnt signaling may be a promising therapeutic target for triple-negative breast cancer, we investigated whether β-catenin was necessary for tumorigenic behaviors in vivo and in vitro. β-catenin expression level was significantly reduced in two human triple-negative breast cancer cell lines, MDA-MB-231 and HCC38, using lentiviral delivery of β-catenin-specific small hairpin RNAs (shRNAs). Upon implantation of the cells in the mammary fat pad of immunocompromised mice, we found that β-catenin shRNA HCC38 cells formed markedly smaller tumors than control cells and grew much more slowly. In in vitro assays, β-catenin silencing significantly reduced the percentage of Aldefluor-positive cells, a read-out of the stem-like cell population, as well as the expression of stem cell-related target genes including Bmi-1 and c-Myc. β-catenin-knockdown cells were also significantly impaired in their ability to migrate in wound-filling assays and form anchorage-independent colonies in soft agar. β-catenin-knockdown cells were more sensitive to chemotherapeutic agents doxorubicin and cisplatin. Collectively, these data suggest that β-catenin is required for triple-negative breast cancer development by controlling numerous tumor-associated properties, such as migration, stemness, anchorage-independent growth and chemosensitivity.