[6]-Gingerol-Derived Semi-Synthetic Compound SSi6 Inhibits Tumor Growth and Metastatic Dissemination in Triple-Negative Breast Cancer Xenograft Models

Breast cancer metastasis is the most common cause of cancer death in women worldwide. Triple-negative breast cancers (TNBC) form a heterogeneous group of tumors that have higher relapse rates and poorer survival compared to other breast cancer subtypes. Thus, this work reports the antitumor and antimetastatic activities of a [6]-gingerol-derived semi-synthetic compound named SSi6 on MDA-MB-231 TNBC cells using xenograft models. SSi6 did not cause toxic effects in vivo as demonstrated by body weight and hematological and histological evaluations. From the orthotopic xenograft model, we demonstrated that SSi6 slows and inhibits the growth of the primary tumor, as well as prevents metastatic spontaneous progression from lymph nodes to the lungs. Moreover, a second xenograft model with resection of the primary tumor showed that SSi6 also blocks the progression of metastases from the lymph nodes to other visceral organs. Taken together, our results demonstrate that SSi6 is a promising compound to be investigated in other preclinical and clinical models to be applied as a complementary therapy for TNBC.

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Abstract PD8-05: Single-cell analysis of breast cancer metastasis using patient-derived xenograft model reveals clonal relationship between primary tumor and its metastases

10.1158/1538-7445.sabcs19-pd8-05 ◽

2020 ◽

Author(s):

Hakwoo Lee ◽

Farhia Kabeer ◽

Ciara O'Flanagan ◽

Jazmine Brimhall ◽

Justina Biele ◽

...

Keyword(s):

Breast Cancer ◽

Single Cell ◽

Primary Tumor ◽

Cancer Metastasis ◽

Single Cell Analysis ◽

Xenograft Model ◽

Breast Cancer Metastasis ◽

Cell Analysis ◽

Clonal Relationship ◽

Patient Derived Xenograft

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Targeting Monoacylglycerol Lipase in Triple Negative Breast Cancer Reduced Tumor-Associated Inflammation, Tumor Growth and Tumor Colonization in the Brain

10.21203/rs.3.rs-1072053/v1 ◽

2021 ◽

Author(s):

Othman Benchama ◽

Sergiy Tyukhtenko ◽

Michael S. Malamas ◽

Mark K. Williams ◽

Alexandros Makriyannis ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Metastasis ◽

Triple Negative ◽

Breast Cancer Metastasis ◽

Monoacylglycerol Lipase ◽

Breast Cancers ◽

Novel Treatments ◽

The Brain

Abstract While the prevalence of breast cancer metastasis in the brain is significantly higher in triple negative breast cancers (TNBCs), there is a lack of novel and/or improved therapies for these patients. Monoacylglycerol lipase (MAGL) is a hydrolase involved in lipid metabolism that catalyzes the degradation of 2-arachidonoylglycerol (2-AG) linked to generation of pro- and anti-inflammatory molecules. Here, we targeted MAGL in TNBCs, using the selective MAGL inhibitor AM9928 (hMAGL IC50 = 9nM, with prolonged pharmacodynamic effects of 46 hours residence time). AM9928 blocked TNBC cell adhesion and transmigration across human brain microvascular endothelial cells (HBMECs) in 3D co-cultures. In addition, AM9928 inhibited the secretion of IL-6, IL-8, and VEGF-A from TNBC cells. TNBC-derived exosomes activated HBMECs resulting in secretion of elevated levels of IL-8 and VEGF, which were inhibited by AM9928. Knockdown of MAGL by siRNA or treatment with AM9928 increased the expression of the adherent junction E-cadherin, known to be regulated by MAGL. Using in vivo studies of syngeneic GFP-4T1-BrM5 mammary tumor cells, AM9928 inhibited tumor growth in the mammary fat pads and attenuated blood brain barrier (BBB) permeability changes, resulting in reduced TNBC colonization in brain. Together, these results support the potential clinical application of MAGL inhibitors as novel treatments for TNBC.

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In Vivo Xenograft Models of Breast Cancer Metastasis

Breast Cancer Research Protocols ◽

10.1385/1-59259-969-9:479 ◽

2006 ◽

pp. 479-488

Author(s):

Ursula Valentiner ◽

Susan A. Brooks ◽

Udo Schumacher

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Xenograft Models

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Ginsenoside 20(S)-protopanaxadiol inhibits triple-negative breast cancer metastasis in vivo by targeting EGFR-mediated MAPK pathway

Pharmacological Research ◽

10.1016/j.phrs.2019.02.003 ◽

2019 ◽

Vol 142 ◽

pp. 1-13 ◽

Cited By ~ 9

Author(s):

Bo Peng ◽

Rong He ◽

Qihua Xu ◽

Yifei Yang ◽

Qin Hu ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

Mapk Pathway ◽

Breast Cancer Metastasis

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Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition

Scientific Reports ◽

10.1038/s41598-021-91344-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Elizabeth Garcia ◽

Ismat Luna ◽

Kaya L. Persad ◽

Kate Agopsowicz ◽

David A. Jay ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

Breast Cancer Metastasis ◽

Boyden Chamber ◽

Invasive Potential ◽

Mesenchymal Transition ◽

Tnbc Cell

AbstractInvasive breast cancer (BrCa) is predicted to affect 1 in 9 women in a lifetime;1 in 32 will die from this disease. The most aggressive forms of BrCa, basal-like/triple-negative phenotype (TNBC), are challenging to treat and result in higher mortality due high number of metastatic cases. There is a paucity of options for TNBC treatment, which highlights the need for additional innovative treatment approaches. NIH-III mice were injected in the abdominal mammary fat pad with luciferase-expressing derivative of the human TNBC cell line, MDA-MB-231 cells. Animals were gavage-fed with nitrofen at the doses of 1, 3 or 6 mg/kg/alternate days. However, several structural properties/components of nitrofen raise concerns, including its high lipophilicity (cLogP of nearly 5) and a potential toxophore in the form of a nitroarene group. Therefore, we developed analogues of nitrofen which lack the nitro group and/or have replaced the diaryl ether linker with a diarylamine that could allow modulation of polarity. In vitro anti-invasiveness activity of nitrofen analogues were evaluated by quantitative determination of invasion of MDA-MB-231-Luciferase cells through Matrigel using a Boyden chamber. Our in vivo data show that nitrofen efficiently blocks TNBC tumor metastasis. In vitro data suggest that this is not due to cytotoxicity, but rather is due to impairment of invasive capacity of the cells. Further, using an in vitro model of EMT, we show that nitrofen interferes with the process of EMT and promotes mesenchymal to epithelial transformation. In addition, we show that three of the nitrofen analogues significantly reduced invasive potential of TNBC cells, which may, at least partially, be attributed to the analogues’ ability to promote mesenchymal to epithelial-like transformation of TNBC cells. Our study shows that nitrofen, and more importantly its analogues, are significantly effective in limiting the invasive potential of TNBC cell lines with minimal cytotoxic effect. Further, we demonstrate that nitrofen its analogues, are very effective in reversing mesenchymal phenotype to a more epithelial-like phenotype. This may be significant for the treatment of patients with mesenchymal-TNBC tumor subtype who are well known to exhibit high resistance to chemotherapy.

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Methionine deprivation suppresses triple-negative breast cancer metastasis in vitro and in vivo

Oncotarget ◽

10.18632/oncotarget.11615 ◽

2016 ◽

Vol 7 (41) ◽

pp. 67223-67234 ◽

Cited By ~ 32

Author(s):

Hyein Jeon ◽

Jae Hwan Kim ◽

Eunjung Lee ◽

Young Jin Jang ◽

Joe Eun Son ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

Breast Cancer Metastasis

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Minimal dosing of leukocyte targeting TRAIL decreases triple-negative breast cancer metastasis following tumor resection

Science Advances ◽

10.1126/sciadv.aaw4197 ◽

2019 ◽

Vol 5 (7) ◽

pp. eaaw4197 ◽

Cited By ~ 10

Author(s):

Nidhi Jyotsana ◽

Zhenjiang Zhang ◽

Lauren E. Himmel ◽

Fang Yu ◽

Michael R. King

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Primary Tumor ◽

Cancer Metastasis ◽

Triple Negative ◽

Tumor Resection ◽

Breast Cancer Metastasis ◽

Surgical Removal ◽

Secondary Tumors ◽

Tumor Types

Surgical removal of the primary tumor is a common practice in breast cancer treatment. However, postsurgical metastasis poses an immense setback in cancer therapy. Considering that 90% of cancer-related deaths are due to metastasis, antimetastatic therapeutic strategies that can target disseminating tumor cells in the circulation before they can form secondary tumors hold preclinical and clinical potential for cancer patients. Our current work uses a liposomal formulation functionalized with the adhesion receptor E-selectin and the apoptosis-inducing ligand TNF (tumor necrosis factor)–related apoptosis-inducing ligand (TRAIL) to reduce metastasis following tumor resection in an aggressive triple-negative breast cancer (TNBC) mouse model. We demonstrate that minimal administration of E-selectin–TRAIL liposomes can target metastasis in a TNBC model, with primary tumor resection to mimic clinical settings. Our study indicates that TRAIL liposomes, alone or in combination with existing clinically approved therapies, may neutralize distant metastasis of a broad range of tumor types systemically.

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ERβ-mediated induction of cystatins results in suppression of TGFβ signaling and inhibition of triple-negative breast cancer metastasis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1807751115 ◽

2018 ◽

Vol 115 (41) ◽

pp. E9580-E9589 ◽

Cited By ~ 16

Author(s):

Jordan M. Reese ◽

Elizabeth S. Bruinsma ◽

Adam W. Nelson ◽

Igor Chernukhin ◽

Jason S. Carroll ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Targeted Therapies ◽

Cancer Metastasis ◽

Triple Negative ◽

Breast Cancer Metastasis ◽

Tgfβ Signaling

Triple-negative breast cancer (TNBC) accounts for a disproportionately high number of deaths due to a lack of targeted therapies and an increased likelihood of distant recurrence. Estrogen receptor beta (ERβ), a well-characterized tumor suppressor, is expressed in 30% of TNBCs, and its expression is associated with improved patient outcomes. We demonstrate that therapeutic activation of ERβ elicits potent anticancer effects in TNBC through the induction of a family of secreted proteins known as the cystatins, which function to inhibit canonical TGFβ signaling and suppress metastatic phenotypes both in vitro and in vivo. These data reveal the involvement of cystatins in suppressing breast cancer progression and highlight the value of ERβ-targeted therapies for the treatment of TNBC patients.

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