DMF Activates NRF2 to Inhibit the Pro-Invasion Ability of TAMs in Breast Cancer

Tumor-associated macrophages (TAMs) account for more than 50% of the cells in the tumor immune microenvironment of patients with breast cancer. A high TAM density is associated with a poor clinical prognosis. Targeting TAMs is a promising therapeutic strategy because they promote tumor growth, development, and metastasis. In this study, we found that dimethyl formamide (DMF) significantly inhibited the tumor invasion-promoting ability of TAMs in the co-culture system and further showed that DMF functioned by reducing reactive oxygen species (ROS) production in TAMs. The orthotopic 4T1 cell inoculation model and the spontaneous mouse mammary tumor virus-polyoma middle tumor-antigen tumor model were used to evaluate the antitumor effect of DMF. The results showed that DMF significantly inhibited tumor metastasis and increased T-cell infiltration into the tumor microenvironment. Mechanistically, NRF2 activation was necessary for DMF to exert its function, and DMF can play a role in breast cancer as an anticancer drug targeting TAMs.

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CDDO-ME Activates NRF2 to Inhibit The Pro-Invasion Ability of TAMs

10.21203/rs.3.rs-113796/v1 ◽

2020 ◽

Author(s):

Ying Li ◽

Yaxu Jia ◽

Yurong Xu

Keyword(s):

Breast Cancer ◽

Tumor Invasion ◽

Tumor Model ◽

Breast Cancer Patients ◽

Clinical Prognosis ◽

T Cell Infiltration ◽

Promote Tumor Growth ◽

Nrf2 Activation ◽

Tumor Immune Microenvironment ◽

Poor Clinical Prognosis

Abstract Background: Tumor-associated macrophages can account for more than 50% of the cells in the tumor immune microenvironment of breast cancer patients. A high TAM density is related to a poor clinical prognosis. Targeting TAMs is a promising therapeutic strategy since TAMs promote tumor growth, development and metastasis. Results: We found that CDDO-ME significantly inhibited the tumor invasion-promoting ability of TAMs in the coculture system and further showed that CDDO-ME functioned by reducing ROS production in TAMs. The orthotopic 4T1 cell inoculation model and spontaneous MMTV-PyMT tumor model were used to evaluate the antitumor effect of CDDO-ME. The results showed that CDDO-ME significantly inhibited tumor metastasis and increased T cell infiltration into the tumor microenvironment. Mechanistically, NRF2 activation was necessary for CDDO-ME to exert its function. Conclusions: Overall, CDDO-ME can play a role in breast cancer as an anticancer drug targeting TAMs.

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Assessment of the WAP-Myc mouse mammary tumor model for spontaneous metastasis

Scientific Reports ◽

10.1038/s41598-020-75411-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Begüm Utz ◽

Rita Turpin ◽

Johanna Lampe ◽

Jeroen Pouwels ◽

Juha Klefström

Keyword(s):

Breast Cancer ◽

Mammary Tumor ◽

Tumor Model ◽

Primary Tumors ◽

T Cell Infiltration ◽

Cancer Models ◽

Mouse Mammary Tumor ◽

Mammary Tumor Model ◽

Metastatic Process ◽

Mouse Mammary Tumor Model

Abstract Breast cancer is the most common form of cancer in women. Despite significant therapeutic advances in recent years, breast cancer also still causes the greatest number of cancer-related deaths in women, the vast majority of which (> 90%) are caused by metastases. However, very few mouse mammary cancer models exist that faithfully recapitulate the multistep metastatic process in human patients. Here we assessed the suitability of a syngrafting protocol for a Myc-driven mammary tumor model (WAP-Myc) to study autochthonous metastasis. A moderate but robust spontaneous lung metastasis rate of around 25% was attained. In addition, increased T cell infiltration was observed in metastatic tumors compared to donor and syngrafted primary tumors. Thus, the WAP-Myc syngrafting protocol is a suitable tool to study the mechanisms of metastasis in MYC-driven breast cancer.

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Heregulin Co-opts PR Transcriptional Action Via Stat3 Role As a Coregulator to Drive Cancer Growth

Molecular Endocrinology ◽

10.1210/me.2015-1170 ◽

2015 ◽

Vol 29 (10) ◽

pp. 1468-1485 ◽

Cited By ~ 8

Author(s):

Cecilia J. Proietti ◽

Franco Izzo ◽

María Celeste Díaz Flaqué ◽

Rosalía Cordo Russo ◽

Leandro Venturutti ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathways ◽

Mammary Tumor ◽

Mouse Mammary Tumor Virus ◽

Cancer Growth ◽

Mammary Tumor Virus ◽

Mouse Mammary Tumor ◽

Tumor Virus ◽

Virus Promoter

Abstract Accumulated findings have demonstrated the presence of bidirectional interactions between progesterone receptor (PR) and the ErbB family of receptor tyrosine kinases signaling pathways in breast cancer. We previously revealed signal transducer and activator of transcription 3 (Stat3) as a nodal convergence point between said signaling pathways proving that Stat3 is activated by one of the ErbBs' ligands, heregulin (HRG)β1 via ErbB2 and through the co-option of PR as a signaling molecule. Here, we found that HRGβ1 induced Stat3 recruitment to the promoters of the progestin-regulated cell cycle modulators Bcl-XL and p21CIP1 and also stimulated Stat3 binding to the mouse mammary tumor virus promoter, which carries consensus progesterone response elements. Interestingly, HRGβ1-activated Stat3 displayed differential functions on PR activity depending on the promoter bound. Indeed, Stat3 was required for PR binding in bcl-X, p21CIP1, and c-myc promoters while exerting a PR coactivator function on the mouse mammary tumor virus promoter. Stat3 also proved to be necessary for HRGβ1-induced in vivo tumor growth. Our results endow Stat3 a novel function as a coregulator of HRGβ1-activated PR to promote breast cancer growth. These findings underscore the importance of understanding the complex interactions between PR and other regulatory factors, such as Stat3, that contribute to determine the context-dependent transcriptional actions of PR.

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