Krüppel‐like factor 5 (KLF5) is a member of the KLF family. Recent studies have suggested that KLF5 regulates the expression of a large number of new target genes and participates in diverse cellular ...functions, such as stemness, proliferation, apoptosis, autophagy, and migration. In response to multiple signaling pathways, various transcriptional modulation and posttranslational modifications affect the expression level and activity of KLF5. Several transgenic mouse models have revealed the physiological and pathological functions of KLF5 in different cancers. Studies of KLF5 will provide prognostic biomarkers, therapeutic targets, and potential drugs for cancers.
KLF5 is a key transcription factor in cancers. This article reviews the functions, mechanisms, and regulations of KLF5.
Although chemotherapy, targeted therapy and endocrine therapy decrease rate of disease recurrence in most breast cancer patients, many patients exhibit acquired resistance. Hyperactivation of the ...PI3K/AKT/mTOR pathway is associated with drug resistance and cancer progression. Currently, a number of drugs targeting PI3K/AKT/mTOR are being investigated in clinical trials by combining them with standard therapies to overcome acquired resistance in breast cancer. In this review, we summarize the critical role of the PI3K/AKT/mTOR pathway in drug resistance, the development of PI3K/AKT/mTOR inhibitors, and strategies to overcome acquired resistance to standard therapies in breast cancer.
KLF5 (Kruppel-like factor 5) is a basic transcription factor binding to GC boxes at a number of gene promoters and regulating their transcription. KLF5 is expressed during development and, in adults, ...with higher levels in proliferating epithelial cells. The expression and activity of KLF5 are regulated by multiple signaling pathways, including Ras/MAPK, PKC, and TGFβ, and various posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and sumoylation. Consistently, KLF5 mediates the signaling functions in cell proliferation, cell cycle, apoptosis, migration, differentiation, and stemness by regulating gene expression in response to environment stimuli. The expression of KLF5 is frequently abnormal in human cancers and in cardiovascular disease-associated vascular smooth muscle cells (VSMCs). Due to its significant functions in cell proliferation, survival, and differentiation, KLF5 could be a potential diagnostic biomarker and therapeutic target for cancer and cardiovascular diseases.
Ephrin type-A receptor 2 (EphA2), a receptor tyrosine kinase, is overexpressed in human breast cancers often linked to poor patient prognosis. Accumulating evidence demonstrates that EphA2 plays ...important roles in several critical processes associated with malignant breast progression, such as proliferation, survival, migration, invasion, drug resistance, metastasis, and angiogenesis. As its inhibition through multiple approaches can inhibit the growth of breast cancer and restore drug sensitivity, EphA2 has become a promising therapeutic target for breast cancer treatment. Here, we summarize the expression, functions, mechanisms of action, and regulation of EphA2 in breast cancer. We also list the potential therapeutic strategies targeting EphA2. Furthermore, we discuss the future directions of studying EphA2 in breast cancer.
TNFα‐induced protein 2 (TNFAIP2) is a primary response gene of TNFα. TNFAIP2 is highly expressed in immune cells and the urinary bladder. The expression of TNFAIP2 is regulated by multiple ...transcription factors and signalling pathways, including NF‐κB, KLF5 and retinoic acid. Physiologically, TNFAIP2 appears to be a multiple functional mediator not only for inflammation, angiogenesis and tunneling nanotube (TNT) formation but also as a regulator of cell proliferation and migration. The expression of TNFAIP2 is frequently abnormal in human cancers and in infectious diseases. Due to its significant functions in cell proliferation, angiogenesis, migration and invasion, TNFAIP2 could be a potential diagnostic biomarker and therapeutic target for cancer.
The transcription factor KLF5 is highly expressed in basal-like breast cancer and promotes breast cancer cell proliferation, survival, migration and tumour growth. Here we show that, in breast cancer ...cells, KLF5 is stabilized by the deubiquitinase (DUB) BAP1. With a genome-wide siRNA library screen of DUBs, we identify BAP1 as a bona fide KLF5 DUB. BAP1 interacts directly with KLF5 and stabilizes KLF5 via deubiquitination. KLF5 is in the BAP1/HCF-1 complex, and this newly identified complex promotes cell cycle progression partially by inhibiting p27 gene expression. Furthermore, BAP1 knockdown inhibits tumorigenicity and lung metastasis, which can be rescued partially by ectopic expression of KLF5. Collectively, our findings not only identify BAP1 as the DUB for KLF5, but also reveal a critical mechanism that regulates KLF5 expression in breast cancer. Our findings indicate that BAP1 could be a potential therapeutic target for breast and other cancers.
The Yes-associated protein (YAP), an oncoprotein in the Hippo tumor suppressor pathway, regulates tumorigenesis and has been found in a variety of tumors, including breast, ovarian, and ...hepatocellular cancers. Although YAP functions through its WW domains, the YAP WW domain-binding partners have not yet been completely determined. With this study, we demonstrate that YAP functions partially through its binding to KLF5, a transcription factor that promotes breast cell proliferation and survival. YAP interacted with the KLF5 PY motif through its WW domains, preventing the E3 ubiquitin ligase WWP1 from ubiquitinating KLF5. Overexpression of the wild-type YAP but not the WW domain-mutated YAP up-regulated KLF5 protein levels and mRNA expression levels of KLF5 downstream target genes, including FGFBP1 (alias FGF-BP ) and ITGB2 . In addition, knockdown of YAP decreased expression levels of KLF5, FGF-BP, and ITGB2. Depletion of either YAP or KLF5 decreased breast cell proliferation and survival in MCF10A and SW527 breast cell lines, and stable knockdown of either YAP or KLF5 suppressed SW527 xenograft growth in mice. The YAP upstream kinase LATS1 suppressed the KLF5-FGF-BP axis, as well as cell growth through YAP signaling. Both YAP and KLF5 are coexpressed in estrogen receptor ERα-negative breast cell lines. These findings suggest that KLF5 could be an important transcription factor partner for YAP and may contribute to the Hippo pathway.
As a new-generation CDK inhibitor, a CDK4/6 inhibitor combined with endocrine therapy has been successful in the treatment of advanced estrogen receptor-positive (ER+) breast cancer. Although there ...has been overall progress in the treatment of cancer, drug resistance is an emerging cause for breast cancer-related death. Overcoming CDK4/6 resistance is an urgent problem. Overactivation of the cyclin-CDK-Rb axis related to uncontrolled cell proliferation is the main cause of CDK4/6 inhibitor resistance; however, the underlying mechanisms need to be clarified further. We review various resistance mechanisms of CDK4/6 inhibitors in luminal breast cancer. The cell signaling pathways involved in therapy resistance are divided into two groups: upstream response mechanisms and downstream bypass mechanisms. Finally, we discuss possible strategies to overcome CDK4/6 inhibitor resistance and identify novel resistance targets for future clinical application.
The Hippo pathway plays a critical role in cell growth and tumorigenesis. The activity of TEA domain transcription factor 4 (TEAD4) determines the output of Hippo signaling; however, the regulation ...and function of TEAD4 has not been explored extensively. Here, we identified glucocorticoids (GC) as novel activators of TEAD4. GC treatment facilitated glucocorticoid receptor (GR)-dependent nuclear accumulation and transcriptional activation of TEAD4. TEAD4 positively correlated with GR expression in human breast cancer, and high expression of TEAD4 predicted poor survival of patients with breast cancer. Mechanistically, GC activation promoted GR interaction with TEAD4, forming a complex that was recruited to the TEAD4 promoter to boost its own expression. Functionally, the activation of TEAD4 by GC promoted breast cancer stem cells maintenance, cell survival, metastasis, and chemoresistance both
and
. Pharmacologic inhibition of TEAD4 inhibited GC-induced breast cancer chemoresistance. In conclusion, our study reveals a novel regulation and functional role of TEAD4 in breast cancer and proposes a potential new strategy for breast cancer therapy. SIGNIFICANCE: This study provides new insight into the role of glucocorticoid signaling in breast cancer, with potential for clinical translation.
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