Response to mTOR and PI3K inhibitors in enzalutamide-resistant luminal androgen receptor triple-negative breast cancer patient-derived xenografts

Lavigne, Marion; Koning, Leanne de; Botty, Rania El; Némati, Fariba; Naguez, Adnan; Bataillon, Guillaume; Ouine, Bérengère; Dahmani, Ahmed; Montaudon, Élodie; Painsec, Pierre; Château-Joubert, Sophie; Fuhrmann, Laetitia; Larcher, Thibaut; Vacher, Sophie; Chemlali, Walid; Briaux, Adrien; Melaabi, Samia; Vincent‐Salomon, Anne; Guinebretière, Jean Marc; Bièche, Ivan; Marangoni, Elisabetta

doi:10.7150/thno.36182

Cited by 38 publications

(38 citation statements)

References 46 publications

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“…Many researchers have identified multiple specific molecular targets those can be used for TNBC cancer therapy, such as intra-nuclear targets, intracellular targets, cell surface targets, and immune checkpoint modulators [ 24 , 25 ]. Recently, the potential role of lamins in the progression of different cancers has been widely revealed [ 17 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

et al. 2021

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Triple negative breast cancer (TNBC) is a more common type of breast cancer with high distant metastasis and poor prognosis. The potential role of lamins in cancer progression has been widely revealed. However, the function of lamin B2 (LMNB2) in TNBC progression is still unclear. The present study aimed to investigate the role of LMNB2 in TNBC. The cancer genome atlas (TCGA) database analysis and immunohistochemistry (IHC) were performed to examine LMNB2 expression levels. LMNB2 short hairpin RNA plasmid or lentivirus was used to deplete the expression of LMNB2 in human TNBC cell lines including MDA-MB-468 and MDA-MB-231. Alterations in cell proliferation and apoptosis in vitro and the nude mouse tumorigenicity assay in vivo were subsequently analyzed. The human TNBC tissues shown high expression of LMNB2 according to the bioinformation analysis and IHC assays. LMNB2 expression was correlated with the clinical pathological features of TNBC patients, including pTNM stage and lymph node metastasis. Through in vitro and in vivo assays, we confirmed LMNB2 depletion suppressed the proliferation and induced the apoptosis of TNBC cells, and inhibited tumor growth of TNBC cells in mice, with the decrease in Ki67 expression or the increase in caspase-3 expression. In conclusion, LMNB2 may promote TNBC progression and could serve as a potential therapeutic target for TNBC treatment.

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Section: Discussionmentioning

confidence: 99%

Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

et al. 2021

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“…The LAR subtype is especially characterized by positive AR expression and expression of luminal cytokeratins [ 3 ], but that does not implicate that only the LAR subtype is AR-positive. In addition, the LAR subtype has higher AR mRNA levels than other TNBC subtypes and expresses numerous downstream AR targets and coactivators [ 21 ]. Even though AR is expressed at a lower rate in TNBC than in other breast cancers, its presence could still be useful in diagnostic and prognostic evaluation and could provide novel insights important for managing such challenging tumor [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical Implications of Androgen-Positive Triple-Negative Breast Cancer

Brumec

Sobočan

Takač

et al. 2021

Cancers

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This review summarizes the recent findings of a vast array of studies conducted on androgen receptor-positive triple-negative breast cancer (AR-positive TNBC) to provide a better understanding of this specific breast cancer subgroup. AR expression is correlated with higher age, lower histological grade, lower proliferation index Ki-67, spiculated masses, and calcifications on mammography. Studies investigating the correlation between AR expression and lymph node metastasis are highly discordant. In addition, results regarding prognosis are highly contradictory. AR antagonists are a promising novel therapeutic approach in AR-positive TNBC. However, AR signaling pathways should be more investigated in order to understand the influence of AR expression on TNBC more thoroughly.

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“…This “recycling” process enables cells to cope with various stress conditions and maintain cellular homeostasis 9 - 10 . Autophagy participates in the progression of a number of disorders, such as cancer, auto-immune diseases, infection and neurodegeneration 11 - 12 . In the context of cancer progression, it is worth noting that autophagy is considered a “double-edged sword”.…”

Section: Introductionmentioning

confidence: 99%

Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in Triple-negative Breast Cancer

Zhen¹,

Zhao²,

Wang³

et al. 2020

Theranostics

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Background: Triple-negative breast cancer (TNBC) is one of the most prevalent neoplastic diseases worldwide, but efficacious treatments for this pathological condition are still challenging. The lack of an effective targeted therapy also leads to a poor prognosis for patients affected by TNBC. In the present study, we repurposed the distinctive inhibitory effects of flubendazole, a traditional anthelmintic drug, towards the putative modulation of proliferation and migration of TNBC in vitro and in vivo . Methods: According to a series of experimental approaches, including immunofluorescence (IF), immunoblotting (IB), siRNA and GFP-mRFP-LC3 plasmid transfection, respectively, we have found that flubendazole is capable of inducing autophagic cell death and apoptosis, thus exerting some anti-proliferative and anti-migration activity in TNBC cells. The therapeutic effects of flubendazole were evaluated by xenograft mouse models, followed by immunohistochemistry (IHC), IF and IB. Changes in the gene expression profiles of flubendazole-treated TNBC cells were analyzed by RNA sequencing (RNA-seq) and validated by IB. The potential binding mode of flubendazole and EVA1A was predicted by molecular docking and demonstrated by site-directed mutagenesis. Results: We have presently found that flubendazole exhibits a considerable anti-proliferative activity in vitro and in vivo . Mechanistically, the induction of autophagic cell death appears to be pivotal for flubendazole-mediated growth inhibition of TNBC cells, whereas blocking autophagy was able to improve the survival rate and migration ability of flubendazole-treated TNBC cells. Specifically, RNA-seq analysis showed that flubendazole treatment could promote the up-regulation of EVA1A. Flubendazole may regulate autophagy and apoptosis by targeting EVA1A, thus affecting the mechanisms of TNBC proliferation and migration. Furthermore, Thr113 may be the key amino acid residues for the binding of flubendazole to EVA1A. Conclusion: Our results provide novel insights towards the putative anti-cancer efficacy of flubendazole. Furthermore, here we show that flubendazole could serve as a potential therapeutic drug in TNBC. Altogether, this study highlights the possibility of this repurposed autophagic inducer for future cancer treatments.

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Response to mTOR and PI3K inhibitors in enzalutamide-resistant luminal androgen receptor triple-negative breast cancer patient-derived xenografts

Cited by 38 publications

References 46 publications

Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

Clinical Implications of Androgen-Positive Triple-Negative Breast Cancer

Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in Triple-negative Breast Cancer

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