Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts

Mollah, Farhana; Varamini, Pegah

doi:10.3390/biomedicines9121921

Cited by 11 publications

(6 citation statements)

References 176 publications

(282 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CAFs are not targeted by paclitaxel, whereas bioactive PAs ( 1 )–( 4 ) maintain dose-dependent anti-proliferative effects presumably by blocking NFκB and HIF signaling and reducing tumor-promoting CAF activation. Because αSMA positive CAFs have been widely described as tumor-promoting and correlating with worse prognosis [ 44 , 110 ], we assume that mainly paracrine signaling enhances inflammation [ 37 ], i.e., NFκB, which might lead to increased vulnerability of co-culture spheroids to treatment with NFκB-inhibiting PAs.…”

Section: Discussionmentioning

confidence: 99%

“…CAFs support tumor invasion and metastasis by enhanced secretion of extracellular matrix (ECM) components, mainly collagen, and proteases for ECM degradation [ 43 ]. Enhanced collagen type I acts as a physical barrier and correlates with reduced drug response [ 32 , 44 ]. Furthermore, a major role in tumor progression is attributed to the CAF-derived cytokines and growth factors that engage NFκB and HIF pathways [ 30 , 45 ], and correlate with cancer relapse and poor prognosis [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phenanthroindolizidine Alkaloids Isolated from Tylophora ovata as Potent Inhibitors of Inflammation, Spheroid Growth, and Invasion of Triple-Negative Breast Cancer

Reimche

Ariantari

et al. 2022

IJMS

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC), representing the most aggressive form of breast cancer with currently no targeted therapy available, is characterized by an inflammatory and hypoxic tumor microenvironment. To date, a broad spectrum of anti-tumor activities has been reported for phenanthroindolizidine alkaloids (PAs), however, their mode of action in TNBC remains elusive. Thus, we investigated six naturally occurring PAs extracted from the plant Tylophora ovata: O-methyltylophorinidine (1) and its five derivatives tylophorinidine (2), tylophoridicine E (3), 2-demethoxytylophorine (4), tylophoridicine D (5), and anhydrodehydrotylophorinidine (6). In comparison to natural (1) and for more-in depth studies, we also utilized a sample of synthetic O-methyltylophorinidine (1s). Our results indicate a remarkably effective blockade of nuclear factor kappa B (NFκB) within 2 h for compounds (1) and (1s) (IC50 = 17.1 ± 2.0 nM and 3.3 ± 0.2 nM) that is different from its effect on cell viability within 24 h (IC50 = 13.6 ± 0.4 nM and 4.2 ± 1 nM). Furthermore, NFκB inhibition data for the additional five analogues indicate a structure–activity relationship (SAR). Mechanistically, NFκB is significantly blocked through the stabilization of its inhibitor protein kappa B alpha (IκBα) under normoxic as well as hypoxic conditions. To better mimic the TNBC microenvironment in vitro, we established a 3D co-culture by combining the human TNBC cell line MDA-MB-231 with primary murine cancer-associated fibroblasts (CAF) and type I collagen. Compound (1) demonstrates superiority against the therapeutic gold standard paclitaxel by diminishing spheroid growth by 40% at 100 nM. The anti-proliferative effect of (1s) is distinct from paclitaxel in that it arrests the cell cycle at the G0/G1 state, thereby mediating a time-dependent delay in cell cycle progression. Furthermore, (1s) inhibited invasion of TNBC monoculture spheroids into a matrigel®-based environment at 10 nM. In conclusion, PAs serve as promising agents with presumably multiple target sites to combat inflammatory and hypoxia-driven cancer, such as TNBC, with a different mode of action than the currently applied chemotherapeutic drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenanthroindolizidine Alkaloids Isolated from Tylophora ovata as Potent Inhibitors of Inflammation, Spheroid Growth, and Invasion of Triple-Negative Breast Cancer

Reimche

Ariantari

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…Despite diagnostic and therapeutic advances, breast cancer (BC) remains the most prevalent cancer worldwide and continues to account for a substantial number of tumorassociated deaths [1]. The progression of and prognosis for BC and other tumor entities is largely determined by the tumor microenvironment (TME) (i.e., by stromal cells including various immune cells and fibroblasts) [2][3][4]. Amongst the tumor-infiltrating immune cells, tumor-associated macrophages (TAM), predominantly derived from blood monocytes, play a crucial role.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-200c Attenuates the Tumor-Infiltrating Capacity of Macrophages

Raue

Frank

Fuhrmann

et al. 2022

Biology

View full text Add to dashboard Cite

Macrophages constitute a major part of the tumor-infiltrating immune cells. Within the tumor microenvironment, they acquire an alternatively activated, tumor-supporting phenotype. Factors released by tumor cells are crucial for the recruitment of tumor-associated macrophages. In the present project, we aimed to understand the role of hsa-miR-200c-3p (miR-200c) in the interplay between tumor cells and macrophages. To this end, we employed a coculture system of MCF7 breast tumor cells and primary human macrophages and observed the transfer of miR-200c from apoptotic tumor cells to macrophages, which required intact CD36 receptor in macrophages. We further comprehensively determined miR-200c targets in macrophages by mRNA-sequencing and identified numerous migration-associated mRNAs to be downregulated by miR-200c. Consequently, miR-200c attenuated macrophage infiltration into 3-dimensional tumor spheroids. miR-200c-mediated reduction in infiltration further correlated with a miR-200c migration signature comprised of the four miR-200c-repressed, predicted targets PPM1F, RAB11FIB2, RDX, and MSN.

show abstract

“…In contrast, the basal-like subtype of breast cancer, also known as triple-negative breast cancer (TNBC), shows the lowest survival rate and does not have effective treatments yet [ 3 , 4 ]. Recent studies reported that the TNBC subtype is much more difficult to treat than the other subtypes of breast cancer due to the lack of experimental data [ 5 , 6 , 7 ] and the interaction between CTL (cytotoxic T lymphocytes) and TNBC cells [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of Gene Correlation Networks of Breast Cancer Patients Based on Mutations in TP53

Park

Han

2022

Biomolecules

View full text Add to dashboard Cite

Breast cancer is one of the most prevalent cancers in females, with more than 450,000 deaths each year worldwide. Among the subtypes of breast cancer, basal-like breast cancer, also known as triple-negative breast cancer, shows the lowest survival rate and does not have effective treatments yet. Somatic mutations in the TP53 gene frequently occur across all breast cancer subtypes, but comparative analysis of gene correlations with respect to mutations in TP53 has not been done so far. The primary goal of this study is to identify gene correlations in two groups of breast cancer patients and to derive potential prognostic gene pairs for breast cancer. We partitioned breast cancer patients into two groups: one group with a mutated TP53 gene (mTP53) and the other with a wild-type TP53 gene (wtTP53). For every gene pair, we computed the hazard ratio using the Cox proportional hazard model and constructed gene correlation networks (GCNs) enriched with prognostic information. Our GCN is more informative than typical GCNs in the sense that it indicates the type of correlation between genes, the concordance index, and the prognostic type of a gene. Comparative analysis of correlation patterns and survival time of the two groups revealed several interesting findings. First, we found several new gene pairs with opposite correlations in the two GCNs and the difference in their correlation patterns was the most prominent in the basal-like subtype of breast cancer. Second, we obtained potential prognostic genes for breast cancer patients with a wild-type TP53 gene. From a comparative analysis of GCNs of mTP53 and wtTP53, we found several gene pairs that show significantly different correlation patterns in the basal-like breast cancer subtype and obtained prognostic genes for patients with a wild-type TP53 gene. The GCNs and prognostic genes identified in this study will be informative for the prognosis of survival and for selecting a drug target for breast cancer, in particular for basal-like breast cancer. To the best of our knowledge, this is the first attempt to construct GCNs for breast cancer patients with or without mutations in the TP53 gene and to find prognostic genes accordingly.

show abstract

Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts

Cited by 11 publications

References 176 publications

Phenanthroindolizidine Alkaloids Isolated from Tylophora ovata as Potent Inhibitors of Inflammation, Spheroid Growth, and Invasion of Triple-Negative Breast Cancer

Phenanthroindolizidine Alkaloids Isolated from Tylophora ovata as Potent Inhibitors of Inflammation, Spheroid Growth, and Invasion of Triple-Negative Breast Cancer

MicroRNA-200c Attenuates the Tumor-Infiltrating Capacity of Macrophages

Comparative Analysis of Gene Correlation Networks of Breast Cancer Patients Based on Mutations in TP53

Contact Info

Product

Resources

About