KCTD15 Enhances Stem Cell-Like Properties and Promotes Triple-Negative Breast Cancer Progression Through KLF4/β-Catenin Signaling

Sep 23, 2026

Uploaded by Jacob

Triple-negative breast cancer (TNBC) remains an aggressive malignancy with limited therapeutic options and poor prognosis, driving the need for novel targets. This study defines KCTD15 as a functional regulator of TNBC progression via the KLF4/β-catenin signaling axis. KCTD15 is highly expressed in TNBC, correlating with higher grade and worse outcomes. KCTD15 knockdown suppresses proliferation, migration, and stem-like traits while increasing apoptosis, with KLF4-dependent nuclear translocation and β-catenin activation. In vivo, KCTD15 silencing reduces xenograft growth and lowers Ki67, KLF4, and β-catenin, supporting an oncogenic role.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

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Introduction

Triple-negative breast cancer background and unmet needs

KCTD protein family and KCTD15 context in cancer

Study aims and experimental strategy

The FASEB Journal RESEARCH ARTICLE OPEN ACCESS KCTD15 Enhances Stem Cell-Like Properties and Promotes Triple-Negative Breast Cancer Progression Through KLF4/β-Catenin Signaling Liang Yao1 | Wei Sun2 | Jun Xing3 | Jing Feng4 1Department of Breast Surgery, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China | 2Department of General Internal Medicine, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China | 3Department of Breast Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China | 4Department of Breast Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China Correspondence: Jun Xing ([xingjun@sxbqeh.com](xingjun@sxbqeh.com)) | Jing Feng ([fengj117812@163.com](fengj117812@163.com)) Received: 17 September 2025 | Revised: 9 January 2026 | Accepted: 2 February 2026 Keywords: β-catenin signaling | KCTD15 | KLF4 | stem cell-like properties | triple-negative breast cancer ABSTRACT Triple-negative breast cancer (TNBC) remains an aggressive malignancy with limited therapeutic options and poor prognosis, underscoring the critical need for novel therapeutic targets. This investigation elucidates the functional role of the potassium channel tetramerization domain 15 (KCTD15) in TNBC progression, providing mechanistic insights into its potential as a therapeutic target for this challenging disease. KCTD15 exhibited high expression in TNBC tissues, correlating with advanced grade and unfavorable prognosis. Functionally, KCTD15 knockdown in TNBC cell lines (BT-549/MDA-MB-231) markedly suppressed cellular proliferation, migration, and cancer stem cell properties, while concomitantly enhancing apoptosis. Mechanistically, KCTD15 directly interacted with KLF4, facilitating its nuclear translocation and subsequent activation of the β-catenin signaling cascade. Notably, KLF4 knockdown abrogated KCTD15-mediated stemness maintenance and β-catenin pathway activation. In vivo, KCTD15 silencing reduced xenograft tumor growth and downregulated Ki67, KLF4, and β-catenin protein expression in tumor tissues, confirming its oncogenic role through the KLF4/β-catenin axis. Our findings establish KCTD15 as a pivotal regulator ofTNBC stemness through modulation of the KLF4/β-catenin signaling axis. These results provide a robust preclinical rationale for developing therapeutic strategies targeting this molecular axis in TNBC management. 1 | Introduction Breast cancer (BC) remains a leading cause of cancer-related morbidity and mortality among women globally, with persistently elevated incidence and mortality rates posing significant threats to public health. Among BC subtypes, triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. This subtype accounts for approximately 15%–20% of all BC cases [1], distinguishing itself through aggressive biological behavior characterized by poorer prognosis, higher recurrence rates, and increased mortality compared to other BC subtypes [2, 3] . Current therapeutic limitations include resistance to endocrine therapies and HER2-targeted agents, coupled with a lack of standardized treatment protocols in clinical practice [4, 5] . These challenges underscore the urgent need for novel therapeutic strategies to address TNBC management. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use a

FAQs

What role does KCTD15 play in triple-negative breast cancer progression?

KCTD15 functions as an oncogenic regulator that enhances TNBC stem cell-like properties and promotes tumor progression through the KLF4/β-catenin signaling axis.

How does KCTD15 mechanistically activate β-catenin signaling?

KCTD15 directly interacts with KLF4, promoting KLF4 nuclear translocation and subsequent activation of the β-catenin signaling cascade. KLF4 knockdown disrupts KCTD15-mediated stemness maintenance and β-catenin pathway activation.

What evidence supports the therapeutic relevance of targeting KCTD15 in vivo?

In xenograft models, KCTD15 silencing reduces tumor growth and decreases Ki67, KLF4, and β-catenin protein expression in tumor tissues, confirming its oncogenic contribution.

Sep 23, 2026

Uploaded by Jacob