Abstract 4366: Inhibition of late-stage tumor growth of human pancreatic and triple-negative breast cancer by blocking the most downstream “gatekeeper” signaling module, SIAH E3 ligase, in the oncogenic ERBB/ K-RAS signaling pathway

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.

Download Full-text

Entelon® (Vitis vinifera Seed Extract) Prevents Cancer Metastasis via the Downregulation of Interleukin-1 Alpha in Triple-Negative Breast Cancer Cells

Molecules ◽

10.3390/molecules26123644 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3644

Author(s):

Daeun You ◽

Yisun Jeong ◽

Sun Young Yoon ◽

Sung A Kim ◽

Eunji Lo ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Lung Metastasis ◽

Triple Negative Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

Interleukin 1 ◽

Metastatic Potential ◽

Cancer Cell Proliferation ◽

Dependent Pathway

Interleukin-1 (IL1) is a proinflammatory cytokine and promotes cancer cell proliferation and invasiveness in a diversity of cancers, such as breast and colon cancer. Here, we focused on the pharmacological effect of Entelon® (ETL) on the tumorigenesis of triple-negative breast cancer (TNBC) cells by IL1-alpha (IL1A). IL1A enhanced the cell growth and invasiveness of TNBC cells. We observed that abnormal IL1A induction is related with the poor prognosis of TNBC patients. IL1A also increased a variety of chemokines such as CCL2 and IL8. Interestingly, IL1A expression was reduced by the ETL treatment. Here, we found that ETL significantly decreased the MEK/ERK signaling pathway in TNBC cells. IL1A expression was reduced by UO126. Lastly, we studied the effect of ETL on the metastatic potential of TNBC cells. Our results showed that ETL significantly reduced the lung metastasis of TNBC cells. Our results showed that IL1A expression was regulated by the MEK/ERK- and PI3K/AKT-dependent pathway. Taken together, ETL inhibited the MEK/ERK and PI3K/AKT signaling pathway and suppressing the lung metastasis of TNBC cells through downregulation of IL1A. Therefore, we propose the possibility of ETL as an effective adjuvant for treating TNBC.

Download Full-text

DIF-1 inhibits growth and metastasis of triple-negative breast cancer through AMPK-mediated inhibition of the mTORC1-S6K signaling pathway

Oncogene ◽

10.1038/s41388-021-01958-4 ◽

2021 ◽

Author(s):

Fumi Seto-Tetsuo ◽

Masaki Arioka ◽

Koichi Miura ◽

Takeru Inoue ◽

Kazunobu Igawa ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Triple Negative Breast Cancer ◽

Triple Negative

Download Full-text

The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion

Oncogene ◽

10.1038/s41388-021-01798-2 ◽

2021 ◽

Author(s):

Qiuping Xu ◽

Jingwei Zhang ◽

Brian A. Telfer ◽

Hao Zhang ◽

Nisha Ali ◽

...

Keyword(s):

Breast Cancer ◽

Protein Kinase ◽

Tumor Growth ◽

Focal Adhesion ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Metastatic Breast ◽

Adhesion Protein ◽

Focal Adhesion Protein

AbstractThere is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior.

Download Full-text

BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells

Open Life Sciences ◽

10.1515/biol-2020-0054 ◽

2020 ◽

Vol 15 (1) ◽

pp. 501-510

Author(s):

Bin Ma ◽

Wenjia Guo ◽

Meihui Shan ◽

Nan Zhang ◽

Binlin Ma ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Nuclear Localization ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Pi3k Pathway ◽

Pi3k Signaling ◽

T47d Cells ◽

Pi3k Signaling Pathway ◽

Hormone Sensitive

AbstractThis study is to investigate the effect of the PI3K/Akt signaling pathway on the regulation of BRCA1 subcellular localization in triple-negative breast cancer (TNBC) MDA-MB-231 cells and hormone-sensitive T47D cells. We found that heregulin-activated T47D cells showed more nuclear localization of BRCA1, but BRCA1 nuclear localization decreased after the inhibition of the PI3K signaling pathway. In MDA-MB-231 cells, activation or inhibition of the PI3K signaling pathway did not significantly affect cell apoptosis and BRCA1 nuclear translocation (P > 0.05). However, in T47D cells, the activation of the PI3K pathway significantly increased cell apoptosis (P < 0.05). In the heregulin-activated MDA-MB-231 and T47D cells, the phosphorylation of Akt and BRCA1 was significantly increased (P < 0.05), while that was significantly reduced after PI3K pathway inhibition (P < 0.05). The changing trends of the mRNA levels of Akt and BRCA1 in MDA-MB-231 and T47D cells after PI3K pathway activation or inhibition were consistent with the trends of their proteins. In both MDA-MB-231 and T47D cells, BRCA1 phosphorylation is regulated by the PI3K signaling pathway, but the nuclear localization of BRCA1 is different in these two cell lines. Moreover, the apoptosis rates of these two cell lines are different.

Download Full-text

The targetable nanoparticle BAF312@cRGD-CaP-NP represses tumor growth and angiogenesis by downregulating the S1PR1/P-STAT3/VEGFA axis in triple-negative breast cancer

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00904-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Ke Gong ◽

Juyang Jiao ◽

Chaoqun Xu ◽

Yang Dong ◽

Dongxiao Li ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Umbilical Vein ◽

Phosphate Ions ◽

Sphingosine 1 Phosphate ◽

Umbilical Vein Endothelial Cells ◽

Endothelial Growth Factor

Abstract Background Overexpressed vascular endothelial growth factor A (VEGFA) and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) cause unrestricted tumor growth and angiogenesis of breast cancer (BRCA), especially triple-negative breast cancer (TNBC). Hence, novel treatment strategy is urgently needed. Results We found sphingosine 1 phosphate receptor 1 (S1PR1) can regulate P-STAT3/VEGFA. Database showed S1PR1 is highly expressed in BRCA and causes the poor prognosis of patients. Interrupting the expression of S1PR1 could inhibit the growth of human breast cancer cells (MCF-7 and MDA-MB-231) and suppress the angiogenesis of human umbilical vein endothelial cells (HUVECs) via affecting S1PR1/P-STAT3/VEGFA axis. Siponimod (BAF312) is a selective antagonist of S1PR1, which inhibits tumor growth and angiogenesis in vitro by downregulating the S1PR1/P-STAT3/VEGFA axis. We prepared pH-sensitive and tumor-targeted shell-core structure nanoparticles, in which hydrophilic PEG2000 modified with the cyclic Arg-Gly-Asp (cRGD) formed the shell, hydrophobic DSPE formed the core, and CaP (calcium and phosphate ions) was adsorbed onto the shell; the nanoparticles were used to deliver BAF312 (BAF312@cRGD-CaP-NPs). The size and potential of the nanoparticles were 109.9 ± 1.002 nm and − 10.6 ± 0.056 mV. The incorporation efficacy for BAF312 was 81.4%. Results confirmed BAF312@cRGD-CaP-NP could dramatically inhibit tumor growth and angiogenesis in vitro and in MDA-MB-231 tumor-bearing mice via downregulating the S1PR1/P-STAT3/VEGFA axis. Conclusions Our data suggest a potent role for BAF312@cRGD-CaP-NPs in treating BRCA, especially TNBC by downregulating the S1PR1/P-STAT3/VEGFA axis. Graphic abstract

Download Full-text