The membrane-linked adaptor FRS2β fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis

Takeuchi, Yasuto; Kimura, Natsuko; Murayama, Takahiko; Machida, Yukino; Iejima, Daisuke; Nishimura, Tatsunori; Terashima, Minoru; Wang, Yuming; Li, Mengjiao; Sakamoto, Reiko; Yamamoto, Mizuki; Itano, Naoki; Inoue, Yusuke; Ito, Masataka; Yoshida, Nobuaki; Inoue, Jun; Akashi, Koichi; Saya, Hideyuki; Fujita, Koji; Kuroda, Masahiko; Kitabayashi, Issay; Voon, Dominic Chih-Cheng; Suzuki, Takeshi; Tojo, Arinobu; Gotoh, Noriko

doi:10.1073/pnas.2103658118

Cited by 5 publications

(3 citation statements)

References 48 publications

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“…MAP2K4 encodes a member of the MAPK family, and MAP2K4 mutation was identified in breast cancer resistant to AI [45]. Fibroblast growth factor receptor substrate 2 (FRS2) acts upstream of the FGF signaling pathway, is an adaptor protein expressed in a small subset of epithelial cells and triggers a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis [46].…”

Section: Discussionmentioning

confidence: 99%

Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer

Lee

Yost

et al. 2022

Cancers

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Cyclin-dependent kinase 4/6 inhibitors are the standard of care for hormone receptor-positive metastatic breast cancer. This retrospective study reports on genomic biomarkers of CDK 4/6i resistance utilizing genomic data acquired through routine clinical practice. Patients with HR+ MBC treated with palbociclib, ribociclib, or abemaciclib and antiestrogen therapy were identified. Patients were grouped into early (<6 months); intermediate (6–24 months for 0–1 lines; 6–9 months for ≥2 lines); or late progressors (>24 months for 0–1 lines; >9 months PFS for ≥2 lines). NGS and RNA sequencing data were analyzed in association with PFS, and survival analysis was stratified by prior lines of chemotherapy. A total of 795 patients with HR+ MBC treated with CDK 4/6i were identified. Of these, 144 (18%) patients had genomic data and 29 (3.6%) had RNA data. Among the 109 patients who received CDK4/6i as 1st- or 2nd-line therapy, 17 genes showed associations with PFS (p-value ≤ 0.15 and HR ≥ 1.5 or HR < 0.5). Whole transcriptome RNAseq was analyzed for 24/109 (22%) patients with 0–1 prior lines of therapy and 56 genes associated with PFS (HR ≥ 4 or HR ≤ 0.25 and FDR ≤ 0.15). In this retrospective analysis, genomic biomarkers including FGFR1 amplification, PTEN loss, and DNA repair pathway gene mutations showed significant associations with shorter PFS for patients receiving CDK4/6 inhibitor therapy.

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Section: Discussionmentioning

confidence: 99%

Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer

Lee

Yost

et al. 2022

Cancers

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“…Recently, we identified novel molecular mechanisms of inflammatory changes in the development of breast cancer. 67 We used mouse mammary tumor virus (MMTV)‐ErbB2 mice, in which overexpression of the receptor tyrosine kinase ErbB2 in mammary epithelial cells causes disease onset and stepwise progression from hyperplasia to DCIS and IBS. 68 This mouse model recapitulates the development of human breast cancer, particularly that of the ErbB2/HER2‐positive subtype.…”

Section: Erbb2‐frs2β‐nf‐κb Axis‐created Cytokine‐enriched Inflammator...mentioning

confidence: 99%

“…However, the molecular mechanisms underlying inflammatory changes during the initiation of breast cancer remain elusive. Recently, we identified novel molecular mechanisms of inflammatory changes in the development of breast cancer 67 . We used mouse mammary tumor virus (MMTV)‐ErbB2 mice, in which overexpression of the receptor tyrosine kinase ErbB2 in mammary epithelial cells causes disease onset and stepwise progression from hyperplasia to DCIS and IBS 68 .…”

Section: Erbb2‐frs2β‐nf‐κb Axis‐created Cytokine‐enriched Inflammator...mentioning

confidence: 99%

Inflammatory cytokine‐enriched microenvironment plays key roles in the development of breast cancers

Takeuchi

Gotoh

2023

Cancer Science

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As the incidence of breast cancer continues to increase, it is critical to develop prevention strategies for this disease. Inflammation underlies the onset of the disease, and NF‐κB is a master transcription factor for inflammation. Nuclear factor‐κB (NF‐κB) is activated in a variety of cell types, including normal epithelial cells, cancer cells, cancer‐associated fibroblasts (CAFs), and immune cells. Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer, and not all DCIS lesions develop into invasive breast cancers (IBC). Currently, most patients with DCIS undergo surgery with postoperative therapy, although there is a risk of overtreatment. In BRCA mutants, receptor activator of NF‐κB (RANK)‐positive progenitors serve as the cell of origin, and treatment using the RANK monoclonal antibody reduces the risk of IBC. There is still an unmet need to diagnose malignant DCIS, which has the potential to progress to IBC, and to establish appropriate prevention strategies. We recently demonstrated novel molecular mechanisms for NF‐κB activation in premalignant mammary tissues, which include DCIS, and the resultant cytokine‐enriched microenvironment is essential for breast cancer development. On the early endosomes in a few epithelial cells, the adaptor protein FRS2β, forming a complex with ErbB2, carries the IκB kinase (IKK) complex and leads to the activation of NF‐κB, thereby inducing a variety of cytokines. Therefore, the FRS2β‐NFκB axis in the inflammatory premalignant environment could be targetable to prevent IBC. Further analysis of the molecular mechanisms of inflammation in the premalignant microenvironment is necessary to prevent the risk of IBC.

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A novel oral inhibitor for one-carbon metabolism and checkpoint kinase 1 inhibitor as a rational combination treatment for breast cancer

Liu

Chen

Wang

et al. 2021

Biochemical and Biophysical Research Communications

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The membrane-linked adaptor FRS2β fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis

Cited by 5 publications

References 48 publications

Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer

Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer

Inflammatory cytokine‐enriched microenvironment plays key roles in the development of breast cancers

A novel oral inhibitor for one-carbon metabolism and checkpoint kinase 1 inhibitor as a rational combination treatment for breast cancer

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