Targeting PRMT5 through PROTAC for the treatment of triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is currently the most aggressive subtype of breast cancer, characterized by high heterogeneity and strong invasiveness, and currently lacks effective therapies. PRMT5, a type II protein arginine methyltransferase, is upregulated in numerous cancers, including TNBC, and plays a critical role, marked it as an attractive therapeutic target. PROTAC (Proteolysis Targeting Chimeras) is an innovative drug development technology that utilizes the ubiquitin-proteasome system (UPS) to degrade target proteins, which is characterized by higher activity, enhanced safety, lower resistance, and reduced toxicity, offering significant value for clinical translation.

TNFAIP2 promotes HIF1α transcription and breast cancer angiogenesis by activating the Rac1-ERK-AP1 signaling axis.

Angiogenesis is well known to play a critical role in breast cancer. We previously reported that TNFAIP2 activates Rac1 to promote triple-negative breast cancer (TNBC) cell proliferation, migration, and chemoresistance. However, the potential contribution of TNFAIP2 to tumor angiogenesis remains unknown.

SGCE promotes breast cancer stemness by promoting the transcription of FGF-BP1 by Sp1.

Breast cancer stem cells are mainly responsible for poor prognosis, especially in triple-negative breast cancer (TNBC). In a previous study, we demonstrated that ε-Sarcoglycan (SGCE), a type Ⅰ single-transmembrane protein, is a potential oncogene that promotes TNBC stemness by stabilizing EGFR. Here, we further found that SGCE depletion reduces breast cancer stem cells, partially through inhibiting the transcription of FGF-BP1, a secreted oncoprotein.

Angiopoietin-1 promotes triple-negative breast cancer cell proliferation by upregulating carboxypeptidase A4.

Angiopoietin-1 (ANG1) is a pro-angiogenic regulator that contributes to the progression of solid tumors by stimulating the proliferation, migration and tube formation of vascular endothelial cells, as well as the renewal and stability of blood vessels. However, the functions and mechanisms of ANG1 in triple-negative breast cancer (TNBC) are unclear. The clinical sample database shows that a higher level of ANG1 in TNBC is associated with poor prognosis compared to non-TNBC.

RNF126-Mediated MRE11 Ubiquitination Activates the DNA Damage Response and Confers Resistance of Triple-Negative Breast Cancer to Radiotherapy.

Triple-negative breast cancer (TNBC) has higher molecular heterogeneity and metastatic potential and the poorest prognosis. Because of limited therapeutics against TNBC, irradiation (IR) therapy is still a common treatment option for patients with lymph nodes or brain metastasis. Thus, it is urgent to develop strategies to enhance the sensitivity of TNBC tumors to low-dose IR.

Targeting HECTD3-IKKα axis inhibits inflammation-related metastasis.

Metastasis is the leading cause of cancer-related death. The interactions between circulating tumor cells and endothelial adhesion molecules in distant organs is a key step during extravasation in hematogenous metastasis. Surgery is a common intervention for most primary solid tumors.

Human fibroblasts facilitate the generation of iPSCs-derived mammary-like organoids.

Background: Breast cancer is the most common malignancy in women worldwide, and its treatment largely depends on mastectomy. Patients after mastectomy suffer from crippled body image, self-esteem, and quality of life. Post-mastectomy breast reconstruction can improve patients' psychosocial health.

A feedforward circuit between KLF5 and lncRNA KPRT4 contributes to basal-like breast cancer.

Basal-like breast cancer (BLBC) is the most aggressive subtype of breast cancer with a poor prognosis. Long noncoding RNAs (lncRNAs) play critical roles in human cancers. Krüppel-like Factor 5 (KLF5) is a key oncogenic transcription factor in BLBC.

STAMBPL1 promotes breast cancer cell resistance to cisplatin partially by stabilizing MKP-1 expression.

Dual-specificity mitogen-activated protein kinase phosphatase-1 (MKP-1/DUSP1/CL-100) has been documented to promote breast cancer cell survival and chemoresistance. MKP-1 is an unstable protein that is ubiquitinated and degraded via the ubiquitin-proteasome system. However, it is not clear how MKP-1 protein stability is regulated in breast cancer.

YB-1 is a positive regulator of KLF5 transcription factor in basal-like breast cancer.

Y-box binding protein 1 (YB-1) is a well-known oncogene highly expressed in various cancers, including basal-like breast cancer (BLBC). Beyond its role as a transcription factor, YB-1 is newly defined as an epigenetic regulator involving RNA 5-methylcytosine. However, its specific targets and pro-cancer functions are poorly defined.

KLF5-induced lncRNA IGFL2-AS1 promotes basal-like breast cancer cell growth and survival by upregulating the expression of IGFL1.

Basal-like breast cancer (BLBC) is the most malignant subtype of breast cancer and has a poor prognosis. Kruppel-like factor 5 (KLF5) is an oncogenic transcription factor in BLBCs. The mechanism by which KLF5 promotes BLBC by regulating the transcription of lncRNAs has not been fully elucidated.

Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORC1 and scavenging ROS.

Weight loss and cachexia are common problems in colorectal cancer patients; thus, parenteral and enteral nutrition support play important roles in cancer care. However, the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied. In this study, we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival (P < 0.

Isochromanoindolenines suppress triple-negative breast cancer cell proliferation partially via inhibiting Akt activation.

As the most malignant subtype of breast cancers, triple-negative breast cancer (TNBC) lacks effective targeted therapeutics clinically to date. In this study, one lead compound FZU-0025-065 with isochromanoindolenine scaffold was identified by a cell-based screening. Among nine breast cancer cell lines tested, TNBC are the most sensitive cell lines to FZU-0025-065.

Targeting ubiquitin conjugating enzyme UbcH5b by a triterpenoid PC3-15 from Schisandra plants sensitizes triple-negative breast cancer cells to lapatinib.

Increasing evidence suggested that a number of ubiquitin enzymes, including ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, E3 ubiquitin ligases and deubiquitination enzymes contribute to therapeutic resistance in triple-negative breast cancer (TNBC) cells. Inhibition of these enzymes with small molecule inhibitors may restore therapeutic sensitivity. Here, we demonstrated ubiquitin conjugating enzyme UbcH5b strongly supports HECTD3 auto-ubiquitination in vitro.

Mifepristone Derivative FZU-00,003 Suppresses Triple-negative Breast Cancer Cell Growth partially via miR-153-KLF5 axis.

Triple-negative breast cancer (TNBC) is one of the most malignant breast cancers lacking targeted therapeutics currently. We recently reported that mifepristone (MIF), a drug regularly used for abortion, suppresses TNBC cell growth by inhibiting KLF5 expression via inducing miR-153. However, its anticancer efficacy is only modest at high dose.

TNF-α increases breast cancer stem-like cells through up-regulating TAZ expression via the non-canonical NF-κB pathway.

Breast cancer patients often suffer from disease relapse and metastasis due to the presence of breast cancer stem-like cells (BCSCs). Numerous studies have reported that high levels of inflammatory factors, including tumor necrosis factor alpha (TNF-α), promote BCSCs. However, the mechanism by which TNF-α promotes BCSCs is unclear.

USP3 promotes breast cancer cell proliferation by deubiquitinating KLF5.

The Krüppel-like factor 5 (KLF5) transcription factor is highly expressed in basal type breast cancer and promotes breast cancer cell proliferation, survival, migration, and tumorigenesis. KLF5 protein stability is regulated by ubiquitination. In this study, ubiquitin-specific protease 3 (USP3) was identified as a new KLF5 deubiquitinase by genome-wide siRNA library screening.

Ilamycin E, a natural product of marine actinomycete, inhibits triple-negative breast cancer partially through ER stress-CHOP-Bcl-2.

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women in the worldwide. Triple-negative breast cancer (TNBC) has a poor clinical outcome. The antitumor efficacy of Ilamycins, natural products with anti-tuberculosis activity isolated from deep sea-derived Streptomyces atratus, in TNBC has not been investigated, and the mechanisms remain elusive.

CUL7 promotes cancer cell survival through promoting Caspase-8 ubiquitination.

The Cullin 7 (CUL7) gene encodes a member of the cullin family of E3 ubiquitin ligases. Accumulated evidence suggests that CUL7 is oncogenic. However, the mechanism by which CUL7 improves cancer cell survival has not been fully elucidated.

Krüpple-like factor 5 is essential for mammary gland development and tumorigenesis.

Krüpple-like factor 5 (KLF5) is required for the development of the embryo and multiple organs, such as the lung and intestine. KLF5 plays a pro-proliferative and oncogenic role in several carcinomas, including breast cancer. However, its role in normal mammary gland development and oncogenesis has not been elucidated in vivo.

CC chemokine receptor 7 promotes triple-negative breast cancer growth and metastasis.

Metastasis is the leading cause of breast cancer-related death. Chemokine (C-C motif) receptor 7 (CCR7) plays important roles in breast cancer metastasis. However, the role of CCR7 in triple-negative breast cancer (TNBC) has not been fully elucidated.

miR-153 inhibits the migration and the tube formation of endothelial cells by blocking the paracrine of angiopoietin 1 in breast cancer cells.

The sprouting of endothelial cells is the first step of tumor angiogenesis. Our previous study suggests that miR-153 suppresses breast tumor angiogenesis partially through targeting hypoxia-induced factor (HIF1α). In this study, we demonstrated that miR-153 also suppresses the migration and the tube formation of endothelial cells through directly targeting angiopoietin 1 (ANG1) in breast cancer cells.

HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection.

Lysine-63-linked (K63-linked) polyubiquitination of TRAF3 coordinates the engagement of pattern-recognition receptors with recruited adaptor proteins and downstream activator TBK1 in pathways that induce type I IFN. Whether autoubiquitination or other E3 ligases mediate K63-linked TRAF3 polyubiquitination remains unclear. We demonstrated that mice deficient in the E3 ligase gene Hectd3 remarkably increased host defense against infection by intracellular bacteria Francisella novicida, Mycobacterium, and Listeria by limiting bacterial dissemination.

Hypoxia induces miR-153 through the IRE1α-XBP1 pathway to fine tune the HIF1α/VEGFA axis in breast cancer angiogenesis.

It is well documented that hypoxia activates the hypoxia-inducible factor 1-alpha (HIF1α)/vascular endothelial growth factor A (VEGFA) axis to promote angiogenesis in breast cancer. However, it is unclear how this axis is negatively regulated. In this study, we demonstrated that miR-153 directly inhibits expression of HIF1α by binding to the 3'UTR of HIF1A mRNA, as well as suppresses tube formation of primary human umbilical vein endothelial cells (HUVECs) and breast cancer angiogenesis by decreasing the secretion of VEGFA.

Mithramycin A suppresses basal triple-negative breast cancer cell survival partially via down-regulating Krüppel-like factor 5 transcription by Sp1.

As the most malignant breast cancer subtype, triple-negative breast cancer (TNBC) does not have effective targeted therapies clinically to date. As a selective Sp1 inhibitor, Mithramycin A (MIT) has been reported to have anti-tumor activities in multiple cancers. However, the efficacy and the mechanism of MIT in breast cancer, especially TNBC, have not been studied.