Parthenolide and its Analogues: A New Potential Strategy for the Treatment of Triple-Negative Breast Tumors

2020 ◽  
Vol 27 (39) ◽  
pp. 6628-6642
Author(s):  
Thaise Gonçalves Araújo ◽  
Lara Vecchi ◽  
Paula Marynella Alves Pereira Lima ◽  
Everton Allan Ferreira ◽  
Igor Moreira Campos ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Triple Negative ◽  
Breast Tumors ◽  
Systemic Effects ◽  
Breast Cancers ◽  
Antitumor Effects ◽  
Tnbc Cell ◽  
Transcriptional Changes ◽  
Potential Strategy ◽  
Molecular Patterns

Triple Negative Breast Cancers (TNBC) are heterogeneous and aggressive pathologies, with distinct morphological and clinical characteristics associated with their genetic diversity, epigenetics, transcriptional changes and aberrant molecular patterns. Treatment with anti-neoplastic drugs exerts systemic effects with low specificity, and incipient improvement in overall survival due to chemoresistance and recurrence. New alternatives for TNBC treatment are urgent and parthenolide or its analogues have been explored. Parthenolide is a sesquiterpene lactone with promising antitumor effects against TNBC cell lines. This review highlights the importance of parthenolide and its analogue drugs in TNBC treatment.

scholarly journals The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stijn Moens ◽  
Peihua Zhao ◽  
Maria Francesca Baietti ◽  
Oliviero Marinelli ◽  
Delphi Van Haver ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Subtype ◽  
Mitotic Checkpoint ◽  
Breast Cancers ◽  
Checkpoint Kinases ◽  
Xenograft Models ◽  
Potential Strategy ◽  
Shrna Screen ◽  
Resistant Cells

AbstractTriple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.

Rad51 Silencing with siRNA Delivered by Porous Silicon-Based Microparticle Enhances the Anti-Cancer Effect of Doxorubicin in Triple-Negative Breast Cancer

2021 ◽  
Vol 17 (12) ◽  
pp. 2351-2363
Author(s):  
Zeliang Wu ◽  
Lin Zhu ◽  
Junhua Mai ◽  
Haifa Shen ◽  
Rong Xu
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Porous Silicon ◽  
Lung Metastasis ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Tnbc Cell

Due to its high heterogeneity and aggressiveness, cytotoxic chemotherapy is still a mainstay treatment for triple negative breast cancer. Unfortunately, the above mentioned has not significantly ameliorated TNBC patients and induces drug resistance. Exploring the mechanisms underlying the chemotherapy sensitivity of TNBC and developing novel sensitization strategies are promising approaches for improving the prognosis of patients. Rad51, a key regulator of DNA damage response pathway, repairs DNA damage caused by genotoxic agents through “homologous recombination repair.” Therefore, Rad51 inhibition may increase TNBC cell sensitivity to anticancer agents. Based on these findings, we first designed Rad51 siRNA to inhibit the Rad51 protein expression in vitro and evaluated the sensitivity of TNBC cells to doxorubicin. Subsequently, we constructed discoidal porous silicon microparticles (pSi) and encapsulated discoidal 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes/siRad51 (PS-DOPC/siRad51) to explore the synergistic antitumor effects of siRad51 and doxorubicin on two mouse models of TNBC in vivo. Our in vitro studies indicated that siRad51 enhanced the efficacy of DOX chemotherapy and significantly suppressed TNBC cell proliferation and metastasis. This effect was related to apoptosis induction and epithelial to mesenchymal transition (EMT) inhibition. siRad51 altered the expression of apoptosis- and EMT-related proteins. In orthotopic and lung metastasis xenograft models, the administration of PS-DOPC/siRad51 in combination with DOX significantly alleviated the primary tumor burden and lung metastasis, respectively. Our current studies present an efficient strategy to surmount chemotherapy resistance in TNBC through microvector delivery of siRad51.

Co-loading of an anthracycline analogue Pirarubicin and Salinomycin in a 1:3 ratio into Quatramerbiodegradable polymeric nanoparticles synergistically inhibit growth of triple-negative breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15047-e15047
Author(s):  
Surender Kharbanda ◽  
Anees Mohammad ◽  
Sachchidanand Tiwari ◽  
Neha Mehrotra ◽  
Sireesh Appajosyula ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancers ◽  
Mice Model ◽  
Single Drug ◽  
Tnbc Cell ◽  
Dual Drug

e15047 Background: Triple negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers and differ from other types of invasive breast cancers in that they grow and spread faster. TNBCs have limited treatment options and a worse prognosis. Therapy with anthracyclines considered to be one of the most effective agents in the treatment. Unfortunately, resistance to anthracycline therapy is very common due to drug efflux mediated by overexpression of ABC transporter. Pirarubicin (PIRA), an analogue of doxorubicin (DOX), is approved in Japan, Korea and China and is shown to be less cardiotoxic than DOX. Recent studies suggest that cancer stem cells (CSCs) play an important role in tumorigenesis and biology of TNBC. Targeting CSCs may be a promising, novel strategy for the treatment of this aggressive disease. Recent studies have shown that salinomycin (SAL) preferentially targets the viability of CSCs. Methods: SAL and PIRA were co-encapsulated in polylactic acid (PLA)-based block copolymeric nanoparticles (NPs) to efficiently co-deliver these agents to treat TNBC cells. Results: Generated SAL-PIRA co-encapsulated dual drug-loaded NPs showed an average diameter of 110 ± 7 nm, zeta potential of -12.5 mV and PDI of less than 0.25. Both of these anti-cancer agents showed slow and sustained release profile in non-physiological buffer (PBS, pH 7.4) from these dual drug-encapsulated NPs. Additionally, multiple ratios (PIRA:SAL = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug-loaded NPs. The results demonstrate that, in contrast to 1:1 and 3:1, treatment of TNBC cells with 1:3 ratio of PIRA:SAL dual drug-loaded NPs, was associated with significant inhibition of growth in vitro in multiple TNBC cell lines. Interestingly, PIRA:SAL (1:3) was synergistic as compared to either SAL- or PIRA single drug-loaded NPs. The IC50 of PIRA and SAL in single drug-encapsulated NPs is 150 nM and 700 nM respectively in MDA-MB-468. Importantly, the IC50 of PIRA in dual drug-encapsulated NPs dropped down to 30 nM (5-fold). Similar results were obtained in SUM-149 TNBC cell line. Studies are underway to evaluate in vivo biological activity of PIRA:SAL (1:3) on tumor growth in a TNBC xenograft mice model. Conclusions: These results demonstrate that a novel dual drug-loaded NP formulation of PIRA and SAL in a unique ratio of 1:3 represents an approach for successful targeting of CSCs and bulk tumor cells in TNBC and potentially other cancer types.

Prevalence of BRCA2 mutations and other clinical characteristics in women with triple-negative breast cancer.

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 160-160
Author(s):  
Jennifer Chun ◽  
Freya Ruth Schnabel ◽  
Shira Schwartz ◽  
Jessica Billig ◽  
Karen Hiotis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
At Risk ◽  
Genetic Testing ◽  
Clinical Characteristics ◽  
Triple Negative ◽  
Ductal Carcinoma ◽  
Personal History ◽  
Breast Cancers ◽  
History Of ◽  
Brca2 Mutations

160 Background: Triple-negative breast cancers (TNBC) represent 10%–20% of invasive breast cancers. Current guidelines recommend genetic testing for women who are diagnosed with TNBC. Studies have shown that BRCA1 mutations are associated with TNBC, but there is little information on the relationship of BRCA2 mutations and TNBC. The purpose of this study was to look at the clinical characteristics of TNBC compared to non-TNBC in a cohort of women with newly diagnosed breast cancer. Methods: The Breast Cancer Database at our institution was queried for patients with invasive breast cancer. We included the following variables: age, race, BRCA1,2, tumor characteristics, and personal history of breast cancer (PHBC). Statistical analyses included Pearson’s Chi-Square and Fisher’s Exact Tests. Results: Out of a total of 1,332 women, 125 (9%) had TNBC. The median age for both TNBC and non-TNBC was 59 years. Majority of women had early stage breast cancer (92%) with ductal carcinoma (80%). There was a significantly higher proportion of Blacks and Asians with TNBC (p < 0.0001). Women with TNBC had higher Ki-67 (p < 0.0001). Within the TNBC group, there were 12 (29%) patients who tested positive for BRCA1,2 mutation and 23 (8%) who tested positive for BRCA 1,2 mutations in the non-TNBC group. Interestingly, BRCA1 was not associated with TNBC (p = 0.40) and BRCA2 was significantly associated with TNBC (p < 0.0001). We also found a higher proportion of TNBC in women who had a PHBC (p = 0.01). Conclusions: In our study, women with TNBC were similar in age to women who did not have TNBC. We found that the women with TNBC in our cohort had elevated rates of BRCA2 mutations. We also found that women with a personal history of breast cancer were at risk for developing TNBC. This may be related to the use of hormonal therapy that reduces the risk of ER/PR-positive tumors. Women of all ages are at risk for developing TNBC and older age at TNBC should not deter from genetic testing.

Association of hypoxia-induced centrosome amplification with clinical outcomes in triple-negative breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23170-e23170
Author(s):  
Karuna Mittal ◽  
Da Hoon Choi ◽  
Angela Ogden ◽  
Brian D Melton ◽  
Meenakshi Vij Gupta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Triple Negative ◽  
Gene Expression Signature ◽  
Breast Tumors ◽  
Centrosome Amplification ◽  
Strong Positive Correlation ◽  
Breast Cancers ◽  
Tissue Samples ◽  
Hypoxic Conditions ◽  
Cells Cultured

e23170 Background: Centrosome amplification (CA) which refers to presence of supernumerary or abnormally large centrosomes is believed to drive tumor progression by promoting chromosomal instability and the generation of aggressive tumor clones that are more capable of rapid metastasis. Not much is known about factors that drive CA within solid tumors. We have previously shown the existence of rampant CA in triple-negative breast cancers (TNBCs).We report here thatintratumoral hypoxia, which is one of the major contributors to tumor heterogeneity, induces CA in TNBCs via HIF-1α. Methods: We immunohistochemically labeled 24 TNBC and adjacent normal tissue samples for HIF-1α and derived weighted indices (WIs) for nuclear HIF-1α. Adjacent serial sections from the same tumors were immunofluorescently labeled for the centrosomal marker γ-tubulin and CA was determined. Using public microarray datasets (Kao dataset, n = 327), we investigated whether centrosomal gene expression is enriched in breast tumors characterized by a hypoxia gene expression signature. Finally, to test the role of hypoxia in CA induction we exposed cultured TNBC cells (MDA-MB-231 and MDA-MB-468) to hypoxia and overexpressed (OE) or knocked out (KO) HIF-1α and quantitated CA. Results: A strong positive correlation was found between nuclear HIF-1α WI and CA in TNBC samples (Spearman’s rho p = 0.722, p < 0.001), and higher nuclear HIF-1α was associated with worse overall survival (p = 0.041; HR = 1.03). Furthermore, breast tumors with high expression of hypoxia-associated genes exhibited higher expression of centrosomal genes than breast tumors with low expression of hypoxia-associated genes. TNBC cells cultured in hypoxic conditions exhibited ~1.5 fold higher (p < 0.05) CA compared to cells cultured in normoxic conditions. Interestingly, level of CA decreased when HIF-1α KO TNBC cells were exposed to hypoxia; conversely, CA increased when HIF-1α OE TNBC cells were cultured in normoxic conditions. Conclusions: Thus,intratumoral hypoxia drives CA in TNBC via HIF-1α and contributes to poor outcomes. Determination of CA may help identify TNBC patients who could benefit from centrosome declustering drugs and HIF-1α inhibitors.

scholarly journals Epigenetic Priming with Decitabine Augments the Therapeutic Effect of Cisplatin on Triple-Negative Breast Cancer Cells through Induction of Proapoptotic Factor NOXA

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 248
Author(s):  
Wataru Nakajima ◽  
Kai Miyazaki ◽  
Masahiro Sakaguchi ◽  
Yumi Asano ◽  
Mariko Ishibashi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Underlying Mechanism ◽  
Breast Cancers ◽  
Hematopoietic Malignancy ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Tnbc Cell ◽  
Aberrant Dna Methylation ◽  
Induced Apoptosis

Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and its effectiveness in treating TNBCs are not fully understood. We analyzed the effects of decitabine on nine TNBC cell lines and examined genes associated with its cytotoxic effects. According to the effect of decitabine, we classified the cell lines into cell death (D)-type, growth inhibition (G)-type, and resistant (R)-type. In D-type cells, decitabine induced the expression of apoptotic regulators and, among them, NOXA was functionally involved in decitabine-induced apoptosis. In G-type cells, induction of the cyclin-dependent kinase inhibitor, p21, and cell cycle arrest were observed. Furthermore, decitabine enhanced the cytotoxic effect of cisplatin mediated by NOXA in D-type and G-type cells. In contrast, the sensitivity to cisplatin was high in R-type cells, and no enhancing effect by decitabine was observed. These results indicate that decitabine enhances the proapoptotic effect of cisplatin on TNBC cell lines that are less sensitive to cisplatin, indicating the potential for combination therapy in TNBC.

scholarly journals Triple-Negative Breast Cancer Cells Recruit Neutrophils by Secreting TGF-β and CXCR2 Ligands

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuvasree SenGupta ◽  
Lauren E. Hein ◽  
Yang Xu ◽  
Jason Zhang ◽  
Jamie R. Konwerski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Neutrophil Migration ◽  
Breast Tumors ◽  
Malignant Potential ◽  
Tnbc Cell

Tumor associated neutrophils (TANs) are frequently detected in triple-negative breast cancer (TNBC). Recent studies also reveal the importance of neutrophils in promoting tumor progression and metastasis during breast cancer. However, the mechanisms regulating neutrophil trafficking to breast tumors are less clear. We sought to determine whether neutrophil trafficking to breast tumors is determined directly by the malignant potential of cancer cells. We found that tumor conditioned media (TCM) harvested from highly aggressive, metastatic TNBC cells induced a polarized morphology and robust neutrophil migration, while TCM derived from poorly aggressive estrogen receptor positive (ER+) breast cancer cells had no activity. In a three-dimensional (3D) type-I collagen matrix, neutrophils migrated toward TCM from aggressive breast cancer cells with increased velocity and directionality. Moreover, in a neutrophil-tumor spheroid co-culture system, neutrophils migrated with increased directionality towards spheroids generated from TNBC cells compared to ER+ cells. Based on these findings, we next sought to characterize the active factors secreted by TNBC cell lines. We found that TCM-induced neutrophil migration is dependent on tumor-derived chemokines, and screening TCM elution fractions based on their ability to induce polarized neutrophil morphology revealed the molecular weight of the active factors to be around 12 kDa. TCM from TNBC cell lines contained copious amounts of GRO (CXCL1/2/3) chemokines and TGF-β cytokines compared to ER+ cell-derived TCM. TCM activity was inhibited by simultaneously blocking receptors specific to GRO chemokines and TGF-β, while the activity remained intact in the presence of either single receptor inhibitor. Together, our findings establish a direct link between the malignant potential of breast cancer cells and their ability to induce neutrophil migration. Our study also uncovers a novel coordinated function of TGF-β and GRO chemokines responsible for guiding neutrophil trafficking to the breast tumor.

scholarly journals P-Rex1 Expression in Invasive Breast Cancer in relation to Receptor Status and Distant Metastatic Site

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Jonathan D. Marotti ◽  
Kristen E. Muller ◽  
Laura J. Tafe ◽  
Eugene Demidenko ◽  
Todd W. Miller
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Breast Tumors ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Solid Organ ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Receptor Status ◽  
Cancer Subtypes

Background. Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 (P-Rex1) has been implicated in cancer growth, metastasis, and response to phosphatidylinositol 3-kinase (PI3K) inhibitor therapy. The aim of this study was to determine whether P-Rex1 expression differs between primary and metastatic human breast tumors and between breast cancer subtypes. Design. P-Rex1 expression was measured in 133 specimens by immunohistochemistry: 40 and 42 primary breast tumors from patients who did versus did not develop metastasis, respectively, and 51 breast-derived tumors from metastatic sites (36 of which had matching primary tumors available for analysis). Results. Primary breast tumors showed significant differences in P-Rex1 expression based on receptor subtype. ER+ and HER2+ primary tumors showed higher P-Rex1 expression than primary triple-negative tumors. HER2+ metastases from all sites showed significantly higher P-Rex1 expression compared to other metastatic receptor subtypes. Solid organ (i.e., brain, lung, and liver) metastases showed higher P-Rex1 expression compared to bone metastases. Conclusions. P-Rex1 expression is increased in ER+ and HER2+ breast cancers compared to triple-negative tumors. P-Rex1 may be differentially expressed in metastatic tumors based on site and receptor status. The role of P-Rex1 in the development of breast cancer metastases and as a predictive biomarker of therapeutic response warrants further investigation.

scholarly journals Low-Dose and Long-Term Olaparib Treatment Sensitizes MDA-MB-231 and SUM1315 Triple-Negative Breast Cancers Spheroids to Fractioned Radiotherapy

2019 ◽  
Vol 9 (1) ◽  
pp. 64
Author(s):  
Clémence Dubois ◽  
Fanny Martin ◽  
Chervin Hassel ◽  
Florian Magnier ◽  
Pierre Daumar ◽  
...  
Keyword(s):  
Low Dose ◽  
Triple Negative ◽  
Breast Cancer Subtype ◽  
Breast Cancers ◽  
Treatment Protocols ◽  
Tnbc Cell ◽  
Cancer Subtype ◽  
Fractioned Irradiation ◽  
Activity Decrease

The Triple-Negative Breast Cancer subtype (TNBC) is particularly aggressive and heterogeneous. Thus, Poly-ADP-Ribose Polymerase inhibitors were developed to improve the prognosis of patients and treatment protocols are still being evaluated. In this context, we modelized the efficacy of Olaparib (i.e., 5 and 50 µM), combined with fractioned irradiation (i.e., 5 × 2 Gy) on two aggressive TNBC cell lines MDA-MB-231 (BRCAness) and SUM1315 (BRCA1-mutated). In 2D cell culture and for both models, the clonogenicity drop was 95-fold higher after 5 µM Olaparib and 10 Gy irradiation than Olaparib treatment alone and was only 2-fold higher after 50 µM and 10 Gy. Similar responses were obtained on TNBC tumor-like spheroid models after 10 days of co-treatment. Indeed, the ratio of metabolic activity decrease was of 1.2 for SUM1315 and 3.3 for MDA-MB-231 after 5 µM and 10 Gy and of only 0.9 (both models) after 50 µM and 10 Gy. MDA-MB-231, exhibiting a strong proliferation profile and an overexpression of AURKA, was more sensitive to the co-treatment than SUM1315 cell line, with a stem-cell like phenotype. These results suggest that, with the studied models, the potentiation of Olaparib treatment could be reached with low-dose and long-term exposure combined with fractioned irradiation.

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