scholarly journals The testis protein ZNF165 is a SMAD3 cofactor that coordinates oncogenic TGFβ signaling in triple-negative breast cancer

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Zane A Gibbs ◽  
Luis C Reza ◽  
Chun-Chun Cheng ◽  
Jill M Westcott ◽  
Kathleen McGlynn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Transforming Growth Factor ◽  
Zinc Finger Protein ◽  
Xenograft Model ◽  
Transforming Growth Factor Β ◽  
Aberrant Expression ◽  
Orthotopic Xenograft Model

Cancer/testis (CT) antigens are proteins whose expression is normally restricted to germ cells yet aberrantly activated in tumors, where their functions remain relatively cryptic. Here we report that ZNF165, a CT antigen frequently expressed in triple-negative breast cancer (TNBC), associates with SMAD3 to modulate transcription of transforming growth factor β (TGFβ)-dependent genes and thereby promote growth and survival of human TNBC cells. In addition, we identify the KRAB zinc finger protein, ZNF446, and its associated tripartite motif protein, TRIM27, as obligate components of the ZNF165-SMAD3 complex that also support tumor cell viability. Importantly, we find that TRIM27 alone is necessary for ZNF165 transcriptional activity and is required for TNBC tumor growth in vivo using an orthotopic xenograft model in immunocompromised mice. Our findings indicate that aberrant expression of a testis-specific transcription factor is sufficient to co-opt somatic transcriptional machinery to drive a pro-tumorigenic gene expression program in TNBC.

scholarly journals The testis protein ZNF165 is a SMAD3 cofactor that coordinates oncogenic TGFβ signaling in triple-negative breast cancer

2020 ◽  
Author(s):  
Zane A. Gibbs ◽  
Luis C. Reza ◽  
Chun-Chun Cheng ◽  
Jill M. Westcott ◽  
Kathleen McGlynn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Transforming Growth Factor ◽  
Zinc Finger Protein ◽  
Transforming Growth Factor Β ◽  
Aberrant Expression ◽  
Growth And Survival ◽  
Ct Antigens

ABSTRACTCancer/testis (CT) antigens are proteins whose expression is normally restricted to germ cells yet aberrantly activated in tumors, where their functions remain relatively cryptic. Here we report that ZNF165, a CT antigen frequently expressed in triple-negative breast cancer (TNBC), associates with SMAD3 to modulate transcription of transforming growth factor β (TGFβ)-dependent genes and thereby promote growth and survival. In addition, we identify the KRAB zinc finger protein, ZNF446, and its associated tripartite motif protein, TRIM27, as obligate components of the ZNF165-SMAD3 complex that also support tumor cell viability. Importantly, we find that TRIM27 alone is necessary for ZNF165 transcriptional activity and is required for orthotopic tumor growth in vivo. Our findings indicate that aberrant expression of a testis-specific transcription factor is sufficient to co-opt somatic transcriptional machinery to drive a pro-tumorigenic gene expression program.

scholarly journals Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sofia M. Saraiva ◽  
Carlha Gutiérrez-Lovera ◽  
Jeannette Martínez-Val ◽  
Sainza Lores ◽  
Belén L. Bouzo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Skin Barrier ◽  
Zebrafish Embryos ◽  
Biorelevant Media

AbstractTriple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

scholarly journals A Single Low Dose of Eribulin Regressed a Highly Aggressive Triple-negative Breast Cancer in a Patient-derived Orthotopic Xenograft Model

2020 ◽  
Vol 40 (5) ◽  
pp. 2481-2485
Author(s):  
HYE IN LIM ◽  
JUN YAMAMOTO ◽  
SACHIKO INUBUSHI ◽  
HIROTO NISHINO ◽  
YOSHIHIKO TASHIRO ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Low Dose ◽  
Triple Negative ◽  
Xenograft Model ◽  
Orthotopic Xenograft ◽  
Orthotopic Xenograft Model

scholarly journals Engineered IL-7 Receptor Enhances the Therapeutic Effect of AXL-CAR-T Cells on Triple-Negative Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Zhenhui Zhao ◽  
Yan Li ◽  
Wei Liu ◽  
Xun Li
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Target Cells ◽  
Car T Cells ◽  
Car T

Triple-negative breast cancer (TNBC) is a very aggressive malignant type of tumor that currently lacks effective targeted therapies. In hematological malignancies, chimeric antigen receptor T (CAR-T) cells have shown very significant antitumor ability; however, in solid tumors, the efficacy is poor. In order to apply CAR-T cells in the treatment of TNBC, in this study, constitutively activated IL-7 receptor (C7R) that has been reported is used to enhance the antitumor function of constructed CAR-T cells by ourselves. Using in vitro coincubation experiments with target cells and in vivo antitumor experiments in mice, we found that the coexpressed C7R can significantly improve the activation, cell proliferation, and cytotoxicity of CAR-T cells. In addition, the in vivo experiments suggested that the enhanced CAR-T cells displayed significant antitumor activity in a TNBC subcutaneous xenograft model, in which in vivo, the survival time of CAR-T cells was prolonged. Together, these results indicated that CAR-T cells that coexpress C7R may be a novel therapeutic strategy for TNBC.

scholarly journals Molecular Investigation on a Triple Negative Breast Cancer Xenograft Model Exposed to Proton Beams

2020 ◽  
Vol 21 (17) ◽  
pp. 6337 ◽  
Author(s):  
Francesco P. Cammarata ◽  
Giusi I. Forte ◽  
Giuseppe Broggi ◽  
Valentina Bravatà ◽  
Luigi Minafra ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Molecular Response ◽  
Proton Beams ◽  
Therapeutic Choice ◽  
Inaccessible Area ◽  
Surrounding Healthy Tissue

Specific breast cancer (BC) subtypes are associated with bad prognoses due to the absence of successful treatment plans. The triple-negative breast cancer (TNBC) subtype, with estrogen (ER), progesterone (PR) and human epidermal growth factor-2 (HER2) negative receptor status, is a clinical challenge for oncologists, because of its aggressiveness and the absence of effective therapies. In addition, proton therapy (PT) represents an effective treatment against both inaccessible area located or conventional radiotherapy (RT)-resistant cancers, becoming a promising therapeutic choice for TNBC. Our study aimed to analyze the in vivo molecular response to PT and its efficacy in a MDA-MB-231 TNBC xenograft model. TNBC xenograft models were irradiated with 2, 6 and 9 Gy of PT. Gene expression profile (GEP) analyses and immunohistochemical assay (IHC) were performed to highlight specific pathways and key molecules involved in cell response to the radiation. GEP analysis revealed in depth the molecular response to PT, showing a considerable immune response, cell cycle and stem cell process regulation. Only the dose of 9 Gy shifted the balance toward pro-death signaling as a dose escalation which can be easily performed using proton beams, which permit targeting tumors while avoiding damage to the surrounding healthy tissue.

Transforming growth factor-β blockade modulates tumor mechanical microenvironment for enhanced antitumor efficacy of photodynamic therapy

Nanoscale ◽  
2021 ◽  
Author(s):  
Jitang Chen ◽  
Si Li ◽  
Xin Liu ◽  
Sha Liu ◽  
Chen Xiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Photodynamic Therapy ◽  
Growth Factor ◽  
Cancer Treatment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Clinical Settings ◽  
Mechanical Microenvironment

Photodynamic therapy (PDT) is frequently used for cancer treatment in the clinical settings. However, its applications in stroma-rich solid tumors, e.g., triple negative breast cancer, are limited by the abnormal...

scholarly journals A Positive Feedback Loop Between TGFβ and Androgen Receptor Supports Triple-Negative Breast Cancer Anoikis Resistance

Endocrinology ◽  
2020 ◽  
Author(s):  
Emmanuel Rosas ◽  
Justin T Roberts ◽  
Kathleen O’Neill ◽  
Jessica L Christenson ◽  
Michelle M Williams ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Transforming Growth Factor ◽  
Pathway Gene ◽  
Clinical Models ◽  
Tgfβ Pathway

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype with peak recurrence as metastatic disease within the first few years of diagnosis. Androgen receptor (AR) expression is increased in anchorage independent cells in TNBC pre-clinical models. Both AR knockdown and inhibition lead to reduced TNBC invasion in vitro, reduced tumorigenicity and less recurrence in vivo in pre-clinical models. Transforming growth factor β (TGFβ) pathway gene signatures also increased during anchorage independent survival both in vitro and in vivo in pre-clinical models and in circulating tumor cells (CTC) from patients during emergence of chemo resistant disease. We hypothesized that a positive loop between AR and TGFβ signaling facilitates TNBC anchorage independent survival. We find that multiple components of the TGFβ pathway, including TGFβ1 and 3, as well as pathway activity measured by nuclear localization and transcriptional activity of phosphorylated Smad3 (pSmad3), are enhanced in anchorage independent conditions. Further, exogenous TGFβ increased AR protein while TGFβ inhibition decreased AR and TNBC viability, particularly under anchorage independent culture conditions. ChIP-seq experiments revealed AR binding to TGFB1 and SMAD3 regulatory regions in MDA-MB-453 cells. In clinical datasets, TGFB3 and AR positively correlate and high expression of both genes together corresponded to significantly worse recurrence-free and overall survival in both ER negative and basal-like breast cancer. Finally, inhibiting both AR and TGFβ decreased cell survival, particularly under anchorage independent conditions. These findings warrant further investigations into whether combined inhibition of AR and TGFβ pathways might decrease metastatic recurrence rates and mortality from TNBC.

scholarly journals Anti-tumor activity of BET inhibitors in androgen-receptor-expressing triple-negative breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
In Hae Park ◽  
Han Na Yang ◽  
Su Yeon Jeon ◽  
Jung-Ah Hwang ◽  
Min Kyeong Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Androgen Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Bet Inhibitor ◽  
Bet Inhibitors ◽  
Anti Tumor Activity

Abstract Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising several subtypes. Androgen-receptor (AR) signaling has been targeted by several investigational agents in luminal AR subtype TNBCs. Bromodomain (BRD) and extra-terminal motif (BET) protein inhibitors have been shown to attenuate AR signaling in metastatic castration-resistant prostate cancer and to overcome enzalutamide resistance. We demonstrated potent anti-tumor effects of the BET inhibitor JQ1 against AR-positive TNBC cell lines using cell viability and cell cycle analysis. To reveal the mechanisms of JQ1 effects, multiplex gene expression analysis and immunoblotting assays were used. We examined in vivo effects of JQ1 in a xenograft model of AR expressing TNBC. JQ1 exhibited its anti-proliferative activity by inducing apoptosis and cell cycle arrest. JQ1 activity was not mediated by MYC downregulation. Instead, JQ1 blocked the interactions among the ATPase-family AAA-domain-containing 2 protein (ATAD2), BRD2, BRD4, and AR; effectively suppressing the expression of AR associated targets. In addition, JQ1 showed significant anti-tumor activity in vivo in TNBC xenograft mouse models as a monotherapy and in combination with anti-AR therapy. Taken together, our results showed that the BET inhibitor JQ1 is a promising therapeutic agent for the treatment of AR-positive TNBC.

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