Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype?

Du, Fanny Le; Eckhardt, Bedrich L.; Lim, Bora; Litton, Jennifer K.; Moulder, Stacy L.; Meric‐Bernstam, Funda; González-Angulo, Ana M.; Ueno, Naoto T.

doi:10.18632/oncotarget.3849

Cited by 96 publications

(82 citation statements)

References 102 publications

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“…TNBC is a heterogeneous disease [8] with different genome based sub-sets within the subtype. This heterogeneity had been known to limit the outcome of the disease by posing real challenges for identifying targets and detecting driving pathways [42] as well as in translating TNBC gene signatures into clinics [43].…”

Section: Discussionmentioning

confidence: 99%

“…Therapeutic options for patients with TNBC are limited because no pathway-specific targets and associated biomarkers have been established [5–7]. Such a situation is further challenged by the fact that the disease is heterogeneous [8–10]. Although reports have indicated the involvement of certain genes/signaling molecules related to tumorigenic/metastatic pathways [5, 11–13] [14] in this subset of BC, there remains an unmet need for an in-depth study to establish a pathway-specific targeted therapy in TNBC, especially in the context of metastatic setting [15].…”

Section: Introductionmentioning

confidence: 99%

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Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers

Carlson

et al. 2016

Oncotarget

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Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronection-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers

Carlson

et al. 2016

Oncotarget

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“…By contrast, triple negative breast cancer (TNBC), which lacks hormone receptors and HER2, accounts for 13% of all breast cancers. TNBC is most prevalent in racial and ethnic minority women [3] and lacks clinically actionable therapeutic targets [4]. …”

Section: Introductionmentioning

confidence: 99%

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

et al. 2016

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Breast cancer remains a leading cause of cancer-related death in women, and triple negative breast cancer (TNBC) lacks clinically actionable therapeutic targets. Death in mitosis is a tumor suppressive mechanism that occurs in cancer cells experiencing a defective M phase. The orphan estrogen-related receptor beta (ERRβ) is a key reprogramming factor in murine embryonic and induced pluripotent stem cells. In primates, ERRβ is alternatively spliced to produce several receptor isoforms. In cellular models of glioblastoma, short form (ERRβsf) and beta2 (ERRβ2) splice variants differentially regulate cell cycle progression in response to the synthetic agonist DY131, with ERRβ2 driving arrest in G2/M.The goals of the present study are to determine the cellular function(s) of ligand-activated ERRβ splice variants in breast cancer and evaluate the potential of DY131 to serve as an antimitotic agent, particularly in TNBC. DY131 inhibits growth in a diverse panel of breast cancer cell lines, causing cell death that involves the p38 stress kinase pathway and a bimodal cell cycle arrest. ERRβ2 facilitates the block in G2/M, and DY131 delays progression from prophase to anaphase. Finally, ERRβ2 localizes to centrosomes and DY131 causes mitotic spindle defects. Targeting ERRβ2 may therefore be a promising therapeutic strategy in breast cancer.

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“…Therefore, basal DNA damage accumulation in our EMT cultures likely stems from compromised HR. In line with this interpretation, HR‐deficient TNBC cells were demonstrated to frequently display EMT (61), and vice versa , HR factor BRCA1 was reported to suppress EMT (62).…”

Section: Discussionmentioning

confidence: 68%

In vitro model for DNA double‐strand break repair analysis in breast cancer reveals cell type–specific associations with age and prognosis

et al. 2016

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Dysfunction of homologous recombination is a common denominator of changes associated with breast cancer-predisposing mutations. In our previous work, we identified a functional signature in peripheral blood lymphocytes from women who were predisposed that indicated a shift from homologous recombination to alternative, error-prone DNA double-strand break (DSB) repair pathways. To capture both hereditary and nonhereditary factors, we newly established a protocol for isolation and ex vivo analysis of epithelial cells, epithelial-mesenchymal transition cells (EMTs), and fibroblasts from breast cancer specimens (147 patients). By applying a fluorescence-based test system, we analyzed the error-prone DSB repair pathway microhomology-mediated end joining in these tumor-derived cell types and peripheral blood lymphocytes. In parallel, we investigated DNA lesion processing by quantitative immunofluorescence microscopy of histone H2AX phosphorylated on Ser139 focus after radiomimetic treatment. Our study reveals elevated histone H2AX phosphorylated on Ser139 damage removal in epithelial cells, not EMTs, and poly(ADP-ribose)polymerase inhibitor sensitivities, which suggested a DSB repair pathway shift with increasing patient age. Of interest, we found elevated microhomology-mediated end joining in EMTs, not epithelial cells, from patients who received a treatment recommendation of adjuvant chemotherapy, that is, those with high-risk tumors. Our discoveries of altered DSB repair activities in cells may serve as a method to further classify breast cancer to predict responsiveness to adjuvant chemotherapy and/or therapeutics that target DSB repair-dysfunctional tumors.-Deniz, M., Kaufmann, J., Stahl, A., Gundelach, T., Janni, W., Hoffmann, I., Keimling, M., Hampp, S., Ihle, M., Wiesmüller, L. In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis.

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Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype?

Cited by 96 publications

References 102 publications

Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers

Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

In vitro model for DNA double‐strand break repair analysis in breast cancer reveals cell type–specific associations with age and prognosis

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