Loss of ERα and FOXA1 expression in a progression model of luminal type breast cancer: Insights from PyMT transgenic mouse model

Nakshatri,

doi:10.3892/or_00000977

Cited by 9 publications

(3 citation statements)

References 24 publications

(42 reference statements)

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“…To create a model for investigating whether the immunomodulatory function of IL-31 affects tumor progression, we generated stable IL-31-expressing PyMT and EMT6 breast carcinoma cell lines (PyMT-IL-31 and EMT6-IL-31, respectively) using lentiviral transduction. The PyMT breast carcinoma model is used to study Luminal B breast carcinoma, 29 whereas EMT6 model is considered to be triple negative breast carcinoma. 30 Control cells were stably transduced with empty vector to generate PyMT-ev and EMT6-ev cell lines.…”

Section: Il-31 Induces Local and Systemic Antitumor Immunitymentioning

confidence: 99%

IL-31 induces antitumor immunity in breast carcinoma

Kan

Feldman

Timaner

et al. 2020

J Immunother Cancer

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BackgroundImmunomodulatory agents that induce antitumor immunity have great potential for treatment of cancer. We have previously shown that interleukin (IL)-31, a proinflammatory cytokine from the IL-6 family, acts as an antiangiogenic agent. Here, we characterize the immunomodulatory effect of IL-31 in breast cancer.MethodsIn vivo breast carcinoma models including EMT6 and PyMT cell lines were used to analyze the effect of IL-31 on the composition of various immune cells in the tumor microenvironment using high-throughput flow cytometry. In vitro studies using isolated cytotoxic T cells, CD4+ T cells, myeloid-derived suppressor cells (MDSCs) and macrophages were carried out to study IL-31 immunological activity. The generation of recombinant IL-31 bound to IgG backbone was used to test IL-31 therapeutic activity.ResultsThe growth rate of IL-31-expressing breast carcinomas is decreased in comparison with control tumors due, in part, to antitumor immunomodulation. Specifically, cytotoxic T cell activity is increased, whereas the levels of CD4+ T cells, MDSCs, and tumor-associated macrophages are decreased in IL-31-expressing tumors. These cellular changes are accompanied by a cytokine profile associated with antitumor immunity. In vitro, IL-31 directly inhibits CD4+ Th0 cell proliferation, and the expression of Th2 canonical factors GATA3 and IL-4. It also promotes CD8+ T cell activation through inhibition of MDSC activity and motility. Clinically, in agreement with the mouse data, alterations in immune cell composition in human breast cancer biopsies were found to correlate with high expression of IL-31 receptor A (IL-31Ra) . Furthermore, high coexpression of IL-31Ra, IL-2 and IL-4 in tumors correlates with increased survival. Lastly, to study the therapeutic potential of IL-31, a recombinant murine IL-31 molecule was fused to IgG via a linker region (IL-31-L-IgG). This IL-31-L-IgG therapy demonstrates antitumor therapeutic activity in a murine breast carcinoma model.ConclusionsOur findings demonstrate that IL-31 induces antitumor immunity, highlighting its potential utility as a therapeutic immunomodulatory agent.

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Section: Il-31 Induces Local and Systemic Antitumor Immunitymentioning

confidence: 99%

IL-31 induces antitumor immunity in breast carcinoma

Kan

Feldman

Timaner

et al. 2020

J Immunother Cancer

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“…We explored the function of Frmd3 in the MMTV-PyMT mouse model, which develops tumors that exhibit luminal progenitor gene signature profiles and resemble the luminal subtype of human breast cancer ( 41 ). We crossed the Frmd3 −/− mice with MMTV-PyMT mice and obtained PyMT/Frmd3 −/− mice.…”

Section: Resultsmentioning

confidence: 99%

Tumor suppressor FRMD3 controls mammary epithelial cell fate determination via notch signaling pathway

Ma,

Gong,

Sun

et al. 2024

Sci. Adv.

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The luminal-to-basal transition in mammary epithelial cells (MECs) is accompanied by changes in epithelial cell lineage plasticity; however, the underlying mechanism remains elusive. Here, we report that deficiency of Frmd3 inhibits mammary gland lineage development and induces stemness of MECs, subsequently leading to the occurrence of triple-negative breast cancer. Loss of Frmd3 in PyMT mice results in a luminal-to-basal transition phenotype. Single-cell RNA sequencing of MECs indicated that knockout of Frmd3 inhibits the Notch signaling pathway. Mechanistically, FERM domain-containing protein 3 (FRMD3) promotes the degradation of Disheveled-2 by disrupting its interaction with deubiquitinase USP9x. FRMD3 also interrupts the interaction of Disheveled-2 with CK1, FOXK1/2, and NICD and decreases Disheveled-2 phosphorylation and nuclear localization, thereby impairing Notch-dependent luminal epithelial lineage plasticity in MECs. A low level of FRMD3 predicts poor outcomes for breast cancer patients. Together, we demonstrated that FRMD3 is a tumor suppressor that functions as an endogenous activator of the Notch signaling pathway, facilitating the basal-to-luminal transformation in MECs.

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“…On the other hand, inflammation also suppresses ERα signaling in ER-positive breast cancer cells, 8 and loss of ERα has been observed during the progression from benign to invasive carcinoma. 9 In addition, deregulation or loss of ERα expression is one of the mechanisms that have been suggested to confer endocrine resistance in patients with ER-positive breast cancer. 10 Thus, we speculate that the inflammatory circuit described in our study may play an important role in ER-negative breast tumorigenesis and in the development of endocrine resistance in ER-positive breast cancer.…”

mentioning

confidence: 99%