Targeting triple negative breast cancer with histone deacetylase inhibitors

Fedele, Palma; Orlando, Laura; Cinieri, Saverio

doi:10.1080/13543784.2017.1386172

Cited by 70 publications

(50 citation statements)

References 69 publications

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“…We have previously shown that aggressive breast cancer subtypes, such as TNBCs [34–36], specifically claudin-low TNBCs [36], are susceptible to DACi. Treatment with romidepsin and panobinostat reversed the mesenchymal phenotype of TNBCs, in addition to suppressing tumorigenesis and metastasis [35], consistent with findings from other groups [33, 37]. Maintenance of a mesenchymal phenotype is important in TNBC biology; the process through which cells acquire these cellular characteristics, also known as the epithelial-to-mesenchymal transition (EMT), is one proposed mechanism that is integral in the initiation of metastasis.…”

Section: Introductionsupporting

confidence: 74%

“…DACi have emerged as an effective targeted therapy in breast carcinomas in preclinical studies [32], specifically in TNBC subtypes [33]. Our laboratory has extensively evaluated DACi in TNBC cells and tumors [34–36]; we observed different biologic effects on tumorigenesis and metastasis with pan-DAC inhibition compared to class-specific inhibitors [35].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor

Chang¹,

Matossian²,

Elliott³

et al. 2019

Preprint

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29 Metaplastic breast carcinoma (MBC) is a clinically aggressive and rare subtype of breast cancer, 30 with similar features to basal-like breast cancers. Due rapid growth rates and characteristic 31 heterogeneity, MBC is often unresponsive to standard chemotherapies; and novel targeted 32 therapeutic discovery is urgently needed. Histone deacetylase inhibitors (DACi) suppress tumor 33 growth and metastasis through regulation of the epithelial-to-mesenchymal transition axis in 34 various cancers, including basal-like breast cancers. 35 We utilized a new MBC patient-derived xenograft (PDX) to examine the effect of DACi therapy 36 on MBC. Cell morphology, cell cycle-associated gene expressions, transwell migration, and 37 metastasis were evaluated in patient-derived cells and tumors after treatment with romidepsin 38 and panobinostat. Derivations of our PDX model, including cells, spheres, organoids, explants, 39 and in vivo implanted tumors were treated. Finally, we tested the effects of combining DACi 40 with approved chemotherapeutics on relative cell biomass.41 DACi significantly suppressed the total number of lung metastasis in vivo using our PDX model, 42 suggesting a role for DACi in preventing circulating tumor cells from seeding distal tissue sites.43 These data were supported by our findings that DACi reduced cell migration, populations, and 44 expression of mesenchymal-associated genes. While DACi treatment did affect cell cycle-45 regulating genes in vitro, tumor growth was not affected compared to controls. Importantly, gene 46 expression results varied depending on the cellular or tumor system used, emphasizing the 47 importance of using multiple derivations of cancer models in preclinical therapeutic discovery 48 research. Furthermore, DACi sensitized and produced a synergistic effect with approved 49 oncology therapeutics on inherently resistant MBC. 3 50 This study introduced a role for DACi in suppressing the migratory and mesenchymal phenotype 51 of MBC cells through regulation of the epithelial-mesenchymal transition axis and suppression 52 of the CTC population. Preliminary evidence that DACi treatment in combination with MEK1/2 53 inhibitors exerts a synergistic effect on MBC cells was also demonstrated. 4 54 Background 55 Metaplastic breast carcinoma (MBC) is a rare breast cancer subtype, comprising 0.45-1% of all 56 breast cancers. This malignancy is molecularly and histologically heterogeneous, expressing both 57 epithelial and mesenchymal features [1-2]; MBC is commonly classified as the triple negative 58 breast cancer (TNBC) PAM50 subtype due to lack of expression of estrogen or progesterone 59 receptors and amplification of the human epidermal growth factor 2 (HER2/Neu) receptor [3]. 60 Poor clinical outcomes are often associated with this cancer diagnosis: the 5-year survival rates 61 for MBC are 38%-78%, compared to 76-93% for invasive ductal carcinoma [4]. A defining 62 feature of MBC is the rapid tumor growth rate; this aggressive clinical presentation contributes to 63 the lower s...

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Section: Introductionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor

Chang¹,

Matossian²,

Elliott³

et al. 2019

Preprint

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“…Crucial preclinical trials on HDAC inhibitors (panobinostat, vorinostat, and entinostat) exert an anti-proliferative effect on TNBC cells and control tumor growth by multiple mechanisms of action, including apoptosis and regulation of the epithelial to mesenchymal transition (EMT). HDAC inhibitors such as suberoylanilidehydroxamic acid (SAHA), sodium butyrate, mocetinostat, panobinostat, entinostat, YCW1 and N-(2-hydroxyphenyl)-2-propylpentanamide have shown promising therapeutic outcomes against TNBC, especially when they are used in combination with other anticancer agents [29,30].…”

Section: Discussionmentioning

confidence: 99%

Trichostatin A inhibits proliferation of triple negative breast cancer cells by inducing cell cycle arrest and apoptosis

Song

et al. 2018

neo

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Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor outcome. Because of lacking therapeutic targets, chemotherapy is the main treatment option for patients with TNBC. Overexpression of HDACs correlates with tumorigenesis, highlighting the potential of HDACs as therapeutic targets for TNBC. Here we demonstrate that trichostatin A (TSA, a HDAC inhibitor) selectively inhibits the proliferation of TNBC cell lines HCC1806 and HCC38 rather than a normal breast cell line MCF10A. The inhibition of TNBC by TSA is via its roles in inducing cell cycle arrest and apoptosis. TSA treatment leads to decreased expression of CYCLIN D1, CDK4, CDK6 and BCL-XL, but increased P21 expression. Moreover, combination of TSA with doxorubicin has synergistic effects on inhibiting proliferation of HCC1806 and HCC38 cells. Our studies identified a promising epigenetic-based therapeutic strategy that may be implemented in the therapy of fatal human breast cancer.

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“…Histone deacetylase (HDAC) inhibitors were reported to show promising activity in triple‐negative breast cancer . Indeed, linking of tamoxifen to the histone deacetylase inhibitor vorinostat resulted in a conjugate with higher cytotoxicity in MCF‐7 and MDA‐MB‐231 cells than the parent drugs .…”

Section: Pharmacology Of Drug‐drug Conjugatesmentioning

confidence: 99%

“…Histone deacetylase (HDAC) inhibitors were reported to show promising activity in triple-negative breast cancer. 34 Indeed, linking of tamoxifen to the histone deacetylase inhibitor vorinostat resulted in a conjugate with higher cytotoxicity in MCF-7 and MDA-MB-231 cells than the parent drugs. 40 The RU39411-like antiestrogen compound conjugated with doxorubicin exhibited lower IC 50 values (ie, greater potency) compared to doxorubicin only or doxorubicin plus the linker when tested in MCF-7 cells, but not MDA-MB-231 cells.…”

Section: Linker Designmentioning

confidence: 99%

Drug conjugates—an emerging approach to treat breast cancer

Hasan

Leak

Stratford

et al. 2018

Pharmacology Res & Perspec

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Breast cancer treatment using a single drug is associated with a high failure rate due, in part, to the heterogeneity of drug response within individuals, nonspecific target action, drug toxicity, and/or development of resistance. Use of dual‐drug therapies, including drug conjugates, may help overcome some of these roadblocks by more selective targeting of the cancer cell and by acting at multiple drug targets rather than one. Drug‐conjugate approaches include linking drugs to antibodies (antibody‐drug conjugates), radionuclides (radioimmunoconjugates), nanoparticles (nanoparticle‐drug conjugates), or to other drugs (drug‐drug conjugates). Although all of these conjugates might be designed as effective treatments against breast cancer, the focus of this review will be on drug‐drug conjugates because of the increase in versatility of these types of drugs with respect to mode of action at the level of the cancer cell either by creating a novel pharmacophore or by increasing the potency and/or efficacy of the drugs’ effects at their respective molecular targets. The development, synthesis, and pharmacological characteristics of drug‐drug conjugates will be discussed in the context of breast cancer with the hope of enhancing drug efficacy and reducing toxicities to improve patient quality of life.

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Targeting triple negative breast cancer with histone deacetylase inhibitors

Cited by 70 publications

References 69 publications

Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor

Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor

Trichostatin A inhibits proliferation of triple negative breast cancer cells by inducing cell cycle arrest and apoptosis

Drug conjugates—an emerging approach to treat breast cancer

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