Triple Negative Breast Cancer: A Mountain Yet to Be Scaled Despite the Triumphs

Wu, Qitong; Siddharth, Sumit; Sharma, Dipali

doi:10.3390/cancers13153697

Cited by 55 publications

(41 citation statements)

References 249 publications

(314 reference statements)

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“…Triple-negative breast cancer (TNBC) stands out as the most aggressive breast cancer subtype, constituting 10–30% of all breast cancer cases. TNBC is characterized by the absence of estrogen receptor and progesterone receptor, as well as HER2 overexpression, and disproportionally affects women with African or Indian ancestry, who show higher incidence of TNBC compared to other breast cancer subtypes [ 2 ]. TNBC is also associated with poorer prognosis than other subtypes of breast cancer, mainly due to higher frequency of metastasis, higher relapse rates and limited treatment options, with no conventional receptor-targeting therapeutics available compared to other breast cancer subtypes.…”

Section: Introductionmentioning

confidence: 99%

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

et al. 2022

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Pd2Spm is a dinuclear palladium(II)-spermine chelate with promising anticancer properties against triple-negative breast cancer (TNBC), a breast carcinoma subset with poor prognosis and limited treatment options. The present study evaluated the in vitro and in vivo anticancer effects of Pd2Spm compared to the reference metal-based drug cisplatin. Triple-negative breast cancer MDA-MB-231 cells, non-cancerous MCF-12A breast cells and chorioallantoic membrane (CAM) assay were used for antiproliferative, antimigratory and antiangiogenic studies. For an in vivo efficacy study, female CBA nude mice with subcutaneously implanted MDA-MB-231 breast tumors were treated with Pd2Spm (5 mg/kg/day) or cisplatin (2 mg/kg/day) administered intraperitoneally during 5 consecutive days. Promising selective antiproliferative activity of Pd2Spm was observed in MDA-MB-231 cells (IC50 values of 7.3–8.3 µM), with at least 10-fold lower activity in MCF-12A cells (IC50 values of 89.5–228.9 µM). Pd2Spm inhibited the migration of MDA-MB-231 cells, suppressed angiogenesis in CAM and decreased VEGF secretion from MDA-MB-231 cells with similar potency as cisplatin. Pd2Spm-treated mice showed a significant reduction in tumor growth progression, and tumors evidenced a reduction in the Ki-67 proliferation index and number of mitotic figures, as well as increased DNA damage, similar to cisplatin-treated animals. Encouragingly, systemic toxicity (hematotoxicity and weight loss) observed in cisplatin-treated animals was not observed in Pd2Spm-treated mice. The present study reports, for the first time, promising cancer selectivity, in vivo antitumor activity towards TNBC and a low systemic toxicity of Pd2Spm. Thus, this agent may be viewed as a promising Pd(II) drug candidate for the treatment of this type of low-prognosis neoplasia.

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Section: Introductionmentioning

confidence: 99%

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

et al. 2022

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“…Breast cancer is the most common malignancy affecting global females, surpassing lung cancer to become the highest-ranking cancer type in 2020 [ 1 ]. Breast cancer is a heterogeneous entity, and the subtypes grouping could be basing on the expression status of progesterone receptor (PR), oestrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2) in the tumors [ 2 ]. Among them, tumors that do not express all of ER, PR and Her-2 are described as triple-negative breast cancer (TNBC).…”

Section: Introductionmentioning

confidence: 99%

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer

et al. 2022

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Background Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAbNectin-4)-based theranostic pair, 99mTc-HYNIC-mAbNectin-4 and mAbNectin-4-ICG. 99mTc-HYNIC-mAbNectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAbNectin-4-ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth. Methods Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of 99mTc-HYNIC-mAbNectin-4. A photothermal agent (PTA) mAbNectin-4-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAbNectin-4-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAbNectin-4-ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated. Results Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake 99mTc-HYNIC-mAbNectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAbNectin-4-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAbNectin-4-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAbNectin-4-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity. Conclusion mAbNectin-4-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAbNectin-4-mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC.

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“…Successful chemotherapeutic treatments can eliminate cancer by inducing cancer cells to undergo apoptotic cell death [ 35 ], and, ideally, apoptosis is induced by chemotherapeutic agents in all TNBC cells [ 36 , 37 , 38 ]. Unfortunately, most TNBC patients will eventually develop resistance to chemotherapy, evading drug-induced cell death (deregulated apoptosis) and allowing the tumors in most TNBC patients to relapse and advance into metastasis, which is the reason for more than 90% of TNBC patients death [ 39 ]. Therefore, targeting deregulated apoptosis is an attractive approach to TNBC therapy [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

DSTYK Enhances Chemoresistance in Triple-Negative Breast Cancer Cells

Ogbu

Rojas

Weaver

et al. 2021

Cells

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Breast cancer, as the most prevalent cancer in women, is responsible for more than 15% of new cancer cases and about 6.9% of all cancer-related death in the US. A major cause of therapeutic failure in breast cancer is the development of resistance to chemotherapy, especially for triple-negative breast cancer (TNBC). Therefore, how to overcome chemoresistance is the major challenge to improve the life expectancy of breast cancer patients. Our studies demonstrate that TNBC cells surviving the chronic treatment of chemotherapeutic drugs show significantly higher expression of the dual serine/threonine and tyrosine protein kinase (DSTYK) than non-treated parental cells. In our in vitro cellular models, DSTYK knockout via the CRISPR/Cas9-mediated technique results in apoptotic cell death of chemoresistant cells upon drug treatment. Moreover, DSTYK knockout promotes chemotherapeutic drug-induced tumor cell death in an orthotopic mouse model. These findings suggest that DSTYK exerts an important and previously unknown role in promoting chemoresistance. Our studies provide fundamental insight into the role of DSTYK in chemoresistance in TNBC cells and lay the foundation for the development of new strategies targeting DSTYK for improving TNBC therapy.

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Triple Negative Breast Cancer: A Mountain Yet to Be Scaled Despite the Triumphs

Cited by 55 publications

References 249 publications

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer

DSTYK Enhances Chemoresistance in Triple-Negative Breast Cancer Cells

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