Neoadjuvant Chemotherapy of Patients with Early Breast Cancer Is Associated with Increased Detection of Disseminated Tumor Cells in the Bone Marrow

Volmer, Léa L.; Koch, Andrè; Matovina, Sabine; Dannehl, Dominik; Weiß, Martin; Welker, Ganna; Hahn, Markus; Engler, Tobias; Wallwiener, Markus; Walter, Christina; Oberlechner, E; Brucker, Sara Y.; Pantel, Klaus; Hartkopf, Andreas D.

doi:10.3390/cancers14030635

Cited by 9 publications

(6 citation statements)

References 37 publications

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“…Moreover, it has been reported that chemotherapy not only increases MenaINV expression but also increases the density of TMEM doorways [19,55] and potentially increases tumor cell dissemination via the blood circulation. Indeed, a recent study indicates that neoadjuvant chemotherapy in patients with early breast cancer leads to an increase in disseminated tumor cells in the bone marrow and subsequent worse overall survival [56]. Therefore, the dismal five-year survival rate for breast cancer patients with metastatic disease of approximately 26% may be due to chemotherapyinduced cancer cell dissemination and increased cancer burden [54,55,[57][58][59][60].…”

Section: Discussionmentioning

confidence: 99%

Cooperative NF-κB and Notch1 signaling promotes macrophage-mediated MenaINV expression in breast cancer

et al. 2023

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Metastasis is a multistep process that leads to the formation of clinically detectable tumor foci at distant organs and frequently to patient demise. Only a subpopulation of breast cancer cells within the primary tumor can disseminate systemically and cause metastasis. To disseminate, cancer cells must express MenaINV, an isoform of the actin regulatory protein Mena, encoded by the ENAH gene, that endows tumor cells with transendothelial migration activity, allowing them to enter and exit the blood circulation. We have previously demonstrated that MenaINV mRNA and protein expression is induced in cancer cells by macrophage contact. In this study, we discovered the precise mechanism by which macrophages induce MenaINV expression in tumor cells. We examined the promoter of the human and mouse ENAH gene and discovered a conserved NF-κB transcription factor binding site. Using live imaging of an NF-κB activity reporter and staining of fixed tissues from mouse and human breast cancer, we further determined that for maximal induction of MenaINV in cancer cells, NF-κB needs to cooperate with the Notch1 signaling pathway. Mechanistically, Notch1 signaling does not directly increase MenaINV expression, but it enhances and sustains NF-κB signaling through retention of p65, an NF-κB transcription factor, in the nucleus of tumor cells, leading to increased MenaINV expression. In mice, these signals are augmented following chemotherapy treatment and abrogated upon macrophage depletion. Targeting Notch1 signaling in vivo decreased NF-κB signaling activation and MenaINV expression in the primary tumor and decreased metastasis. Altogether, these data uncover mechanistic targets for blocking MenaINV induction that should be explored clinically to decrease cancer cell dissemination and improve survival of patients with metastatic disease.

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Section: Discussionmentioning

confidence: 99%

Cooperative NF-κB and Notch1 signaling promotes macrophage-mediated MenaINV expression in breast cancer

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Moreover, it has been reported that chemotherapy not only increases MenaINV expression but also increases the density of TMEM doorways (19,55) and potentially increases tumor cell dissemination via the blood circulation. Indeed, a recent study indicates that neoadjuvant chemotherapy in patients with early breast cancer leads to an increase of disseminated tumor cells in the bone marrow and subsequent worse overall survival (56). Therefore, the dismal five-year survival rate for breast cancer patients with metastatic disease of approximately 26% may be due to chemotherapyinduced cancer cell dissemination and increased cancer burden (54,55,(57)(58)(59)(60).…”

Section: Discussionmentioning

confidence: 99%

Cooperative NF-κB and Notch1 signaling promotes macrophage-mediated MenaINV expression in breast cancer

Duran

Karagiannis

Chen

et al. 2023

Preprint

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Metastasis is a multistep process that leads to the formation of clinically detectable tumor foci at distant organs and frequently patient demise. Only a subpopulation of breast cancer cells within the primary tumor can disseminate systemically and cause metastasis. To disseminate, cancer cells must express MenaINV, an isoform of the actin-regulatory protein Mena encoded by the ENAH gene that endows tumor cells with transendothelial migration activity allowing them to enter and exit the blood circulation. We have previously demonstrated that MenaINV mRNA and protein expression is induced in cancer cells by macrophage contact. In this study, we discovered the precise mechanism by which macrophages induce MenaINV expression in tumor cells. We examined the promoter of the human and mouse ENAH gene and discovered a conserved NF-κB transcription factor binding site. Using live imaging of an NF-κB activity reporter and staining of fixed tissues from mouse and human breast cancer we further determined that for maximal induction of MenaINV in cancer cell NF-κB needs to cooperate with the Notch1 signaling pathway. Mechanistically, Notch1 signaling does not directly increase MenaINV expression, but it enhances and sustains NF-κB signaling through retention of p65, an NF-κB transcription factor, in the nucleus of tumor cells, leading to increased MenaINV expression. In mice, these signals are augmented following chemotherapy treatment and abrogated upon macrophage depletion. Targeting Notch1 signaling in vivo decreased NF-κB signaling and MenaINV expression in the primary tumor and decreased metastasis. Altogether, these data uncover mechanistic targets for blocking MenaINV induction that should be explored clinically to decrease cancer cell dissemination and improve survival of patients with metastatic disease.

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“…Disseminated tumor cells (DTCs) represent one manifestation of MRD: these cells can be detected in the bone marrow (BM) of 20–30% of patients with early breast cancer (EBC) [ 8 ]. Indeed, the detection of DTCs is associated both with a worse outcome and with locoregional and distant recurrence alike [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Comparing the HER2 Status of the Primary Tumor to That of Disseminated Tumor Cells in Early Breast Cancer

Volmer,

Dannehl,

Matovina

et al. 2024

IJMS

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Breast cancer remains a leading cause of cancer mortality in women globally. Despite advancements in systemic therapy, the risk of distant recurrence persists even after such treatment and may be linked to disseminated tumor cells (DTCs). Variability in molecular characteristics between primary tumors (PTs) and distant metastases underscores the need to comprehensively understand metastatic pathways. This retrospective study investigated discrepancies between HER2 expression in PTs and DTCs and their implications for survival outcomes in 201 early breast cancer (EBC) patients. We found a significant association between HER2 expression in PTs and DTCs when classifying tumors as HER2-high/low/negative. Patients whose HER2 status was discordant between PTs and DTCs exhibited worse distant disease-free survival than those with concordant status. Multivariate analysis confirmed the HER2 status of DTCs as an independent prognostic factor for distant DFS. These findings emphasize the importance of assessing HER2 expression in DTCs and its potential implications for tailored therapy strategies in EBC. Furthermore, prospective trials are needed to validate these findings and explore targeted therapies based on the molecular characteristics of DTCs.

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Neoadjuvant Chemotherapy of Patients with Early Breast Cancer Is Associated with Increased Detection of Disseminated Tumor Cells in the Bone Marrow

Cited by 9 publications

References 37 publications

Cooperative NF-κB and Notch1 signaling promotes macrophage-mediated MenaINV expression in breast cancer

Cooperative NF-κB and Notch1 signaling promotes macrophage-mediated MenaINV expression in breast cancer

Cooperative NF-κB and Notch1 signaling promotes macrophage-mediated MenaINV expression in breast cancer

Comparing the HER2 Status of the Primary Tumor to That of Disseminated Tumor Cells in Early Breast Cancer

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