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Updated: Jul 31, 2025
Isolation and Functional Assessment of Human Breast Cancer Stem Cells from Cell and Tissue Samples
Published on: October 2, 2020
KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer
Jiawen Bu1, Yixiao Zhang1, Sijin Wu1,2
1Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China.
Abstract:
Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromises the Hippo pathway and leads to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identify the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employ a computational approach and discover Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppresses TNBC tumor growth via a mechanism that reactivates the Hippo pathway and decreases TNBC ALDH+ cell stemness and viability.
Insights
Triple negative breast cancer (TNBC) stem cells drive poor outcomes. A newly identified KK-LC-1 pathway promotes TNBC stemness, but the inhibitor Z8 shows promise in suppressing tumor growth by targeting this pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Stem Cell Research
Background:
- Triple negative breast cancer (TNBC) stem cells (BCSCs) resist therapy, leading to poor patient outcomes.
- Aldehyde dehydrogenase 1 (ALDH1) is a key marker and regulator of breast cancer stem cell (BCSC) stemness.
- Targeting upstream regulators of ALDH1-positive (ALDH+) cells is crucial for TNBC tumor suppression.
Purpose of the Study:
- To identify molecular mechanisms controlling stemness in TNBC ALDH+ cells.
- To investigate the role of KK-LC-1 in regulating TNBC stemness via the Hippo pathway.
- To discover and evaluate a small-molecule inhibitor targeting the identified pathway for TNBC therapy.
Main Methods:
- Investigated the interaction between KK-LC-1 and FAT1 in TNBC ALDH+ cells.
- Analyzed the impact of KK-LC-1 on the Hippo pathway, YAP1 translocation, and ALDH1A1 transcription.
- Utilized a computational approach to identify Z839878730 (Z8) as a KK-LC-1 inhibitor.
- Assessed the efficacy of Z8 in suppressing TNBC tumor growth, stemness, and viability in vitro and in vivo.
Main Results:
- KK-LC-1 binds FAT1, promoting its degradation and compromising the Hippo pathway, leading to YAP1 nuclear translocation and ALDH1A1 transcription.
- The KK-LC-1-FAT1-Hippo-ALDH1A1 pathway was identified as a critical regulator of TNBC stemness.
- The small molecule Z8 was identified to disrupt KK-LC-1 and FAT1 binding.
- Z8 treatment reactivated the Hippo pathway, reduced TNBC ALDH+ cell stemness, and suppressed tumor growth.
Conclusions:
- The KK-LC-1-FAT1-Hippo-ALDH1A1 pathway is a key driver of stemness in TNBC ALDH+ cells.
- Z8 represents a potential therapeutic agent for TNBC by targeting this pathway.
- Further investigation of Z8 could lead to novel treatment strategies for TNBC patients with poor prognoses.
