Exploratory investigation of PSCA-protein expression in primary breast cancer patients reveals a link to HER2/neu overexpression

Link, Theresa; Kuithan, Friederike; Ehninger, Armin; Kuhlmann, Jan Dominik; Kramer, Michael; Werner, A.; Gatzweiler, A.; Richter, Barbara; Ehninger, Gerhard; Baretton, Gustavo; Bachmann, Michael; Wimberger, Pauline; Friedrich, Katrin

doi:10.18632/oncotarget.17523

Cited by 12 publications

(16 citation statements)

References 48 publications

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“…When miRNAs with negative coefficients intersected with upregulated genes, two miRNA: mRNA pairs targeted the same PSCA gene, i.e., hsa-let-7b-5p: PSCA and hsa-mir-146a-5p: PSCA. Our results show that reduced let-7b and mir-146a expression could account for a higher expression PSCA, which has been shown to correlate with unfavorable histological features and HER2/neu overexpression in breast cancer, although there was no association of PSCA with patients' prognosis [95].…”

Section: Discussionmentioning

confidence: 62%

An Eleven-microRNA Signature Related to Tumor-Associated Macrophages Predicts Prognosis of Breast Cancer

Jayasingam

Citartan

Zin

et al. 2022

IJMS

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The dysregulation of microRNAs (miRNAs) has been known to play important roles in tumor development and progression. However, the understanding of the involvement of miRNAs in regulating tumor-associated macrophages (TAMs) and how these TAM-related miRNAs (TRMs) modulate cancer progression is still in its infancy. This study aims to explore the prognostic value of TRMs in breast cancer via the construction of a novel TRM signature. Potential TRMs were identified from the literature, and their prognostic value was evaluated using 1063 cases in The Cancer Genome Atlas Breast Cancer database. The TRM signature was further validated in the external Gene Expression Omnibus GSE22220 dataset. Gene sets enrichment analyses were performed to gain insight into the biological functions of this TRM signature. An eleven-TRM signature consisting of mir-21, mir-24-2, mir-125a, mir-221, mir-22, mir-501, mir-365b, mir-660, mir-146a, let-7b and mir-31 was constructed. This signature significantly differentiated the high-risk group from the low-risk in terms of overall survival (OS)/ distant-relapse free survival (DRFS) (p value < 0.001). The prognostic value of the signature was further enhanced by incorporating other independent prognostic factors in a nomogram-based prediction model, yielding the highest AUC of 0.79 (95% CI: 0.72–0.86) at 5-year OS. Enrichment analyses confirmed that the differentially expressed genes were mainly involved in immune-related pathways such as adaptive immune response, humoral immune response and Th1 and Th2 cell differentiation. This eleven-TRM signature has great potential as a prognostic factor for breast cancer patients besides unravelling the dysregulated immune pathways in high-risk breast cancer.

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Section: Discussionmentioning

confidence: 62%

An Eleven-microRNA Signature Related to Tumor-Associated Macrophages Predicts Prognosis of Breast Cancer

Jayasingam

Citartan

Zin

et al. 2022

IJMS

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“…For targeted delivery of TLR3 agonist to tumor cells we sought to employ this platform technology and to couple biotinylated nucleic acid-based TLR agonists, in particular dsRNA, to tumor-specific antibodies via consecutive bio-conjugation to neutravidin. As a model tumor-antigen we choose PSCA, a surface protein which is found on several tumor entities 18–24 . For a potential clinical application we furthermore engineered an humanized scFv based on our recently described mono-biotinylated anti-PSCA scFv(AM1)-P-BAP 26 .…”

Section: Resultsmentioning

confidence: 99%

“…4d the incubation of cells with chlorpromazine, which blocks clathrin-dependent endocytosis 22 , markedly inhibited SEAP activity in RICIA-treated cells. Weaker but still significant effects were observed when cells were treated with filipin III, an inhibitor of caveolae-dependent and lipid raft-mediated endocytosis 24 . Whether the targeted delivery of TLR3 into endosomes of target cells can induce a type I-interferon response was investigated by enzyme-linked immunosorbent assay.…”

Section: Resultsmentioning

confidence: 99%

“…PSCA represents an associated GPI-anchored cell surface antigen 15–18 which is expressed in normal prostate-specific tissue and overexpressed in prostate cancer specimens including both, high-grade prostatic intraepithelial neoplasia and androgen-dependent/-independent tumors 18 . PSCA was also found to be expressed in prostate cancer metastases 19 and in prostate-unrelated carcinomas such as renal clear cell carcinoma 20 , transitional cell carcinoma 21 , pancreatic adenocarcinoma 22 , glioblastoma, and HER2/neu-overexpressing breast cancer 23,24 . To be closer to a clinical application we furthermore humanized the PSCA-specific scFv(AM1) 25 by engrafting the complimentary determining regions (CDRs) into human Ig germline genes.…”

Section: Introductionmentioning

confidence: 99%

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Targeted delivery of TLR3 agonist to tumor cells with single chain antibody fragment-conjugated nanoparticles induces type I-interferon response and apoptosis

Schau

Michen

Hagstotz

et al. 2019

Sci Rep

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Application of Toll-like receptor (TLR) agonists is a promising approach to treat cancer. In particular, nucleic acid-based TLR agonists such as short ssRNA and dsRNA molecules, which activate endosomal TLRs, can be delivered to tumors by use of nanoparticle delivery systems. However, such delivery systems bear unspecific side effects and poor pharmacokinetics. To overcome these limitations we developed a system for targeted delivery of a 50 bp dsRNA TLR3 agonist (Riboxxol) to treat PSCA-positive tumor cells, which consists of neutravidin conjugated to mono-biotinylated dsRNA and to humanized mono-biotinylated anti-PSCA single chain antibody derivative scFv(h-AM1)-BAP. The assembly of the components resulted in the formation of nanoparticle-like immunoconjugates designated Rapid Inducer of Cellular Inflammation and Apoptosis (RICIA). Anti-PSCA-RICIA exclusively delivered Riboxxol to PSCA-positive tumor cells as well as subcutaneous tumors. Uptake of anti-PSCA-RICIA induced a type I-interferon response and apoptosis in HEK-Blue hTLR3/PSCA reporter cells and PSCA-positive HT1376 bladder cancer cells in vitro . No such effects were observed when using RICIA coupled to an unspecific control antibody or when using Riboxxol alone. Treatment of HT1376 xenografts in immune-deficient hosts with targeted delivery of TLR3 agonist did not induce adverse effects and only modestly inhibited tumor growth when compared to controls. These results suggest promising activation of innate immune response and apoptosis upon selective delivery of TLR3 agonists in tumor cells. Yet, further studies using syngeneic and orthotopic tumor models are needed to fully exploit the potential of RICIA immunoconjugates.

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“…Prostate stem cell antigen (PSCA) is a member of the Thy-1/Ly-6 family that encodes a 123-amino acid GPI-anchored cell surface protein (Table 1) [49]. Upregulated PSCA expression was found in breast cancer patients and was associated with unfavourable histopathological grade, increased Ki67 proliferation index and HER2/neu receptor status [49]. Patients with PSCA-positive invasive micropapillary carcinoma (IMPC) of the breast had decreased DFS compared to PSCA-negative IMPC patients [50].…”

Section: Ctas Associated With Worse Outcome In Tnbcmentioning

confidence: 99%

Cancer-Testis Antigens in Triple-Negative Breast Cancer: Role and Potential Utility in Clinical Practice

Lam

Tien

Joseph

et al. 2021

Cancers

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Breast cancer cells commonly express tumour-associated antigens that can induce immune responses to eradicate the tumour. Triple-negative breast cancer (TNBC) is a form of breast cancer lacking the expression of hormone receptors and cerbB2 (HER2) and tends to be more aggressive and associated with poorer prognoses due to the limited treatment options. Characterisation of biomarkers or treatment targets is thus of great significance in revealing additional therapeutic options. Cancer-testis antigens (CTAs) are tumour-associated antigens that have garnered strong attention as potential clinical biomarkers in targeted immunotherapy due to their cancer-restricted expressions and robust immunogenicity. Previous clinical studies reported that CTAs correlated with negative hormonal status, advanced tumour behaviour and a poor prognosis in a variety of cancers. Various studies also demonstrated the oncogenic potential of CTAs in cell proliferation by inhibiting cell death and inducing metastasis. Multiple clinical trials are in progress to evaluate the role of CTAs as treatment targets in various cancers. CTAs hold great promise as potential treatment targets and biomarkers in cancer, and further research could be conducted on elucidating the mechanism of actions of CTAs in breast cancer or combination therapy with other immune modulators. In the current review, we summarise the current understandings of CTAs in TNBC, addressing the role and utility of CTAs in TNBC, as well as discussing the potential applications and advantage of incorporating CTAs in clinical practise.

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Exploratory investigation of PSCA-protein expression in primary breast cancer patients reveals a link to HER2/neu overexpression

Cited by 12 publications

References 48 publications

An Eleven-microRNA Signature Related to Tumor-Associated Macrophages Predicts Prognosis of Breast Cancer

An Eleven-microRNA Signature Related to Tumor-Associated Macrophages Predicts Prognosis of Breast Cancer

Targeted delivery of TLR3 agonist to tumor cells with single chain antibody fragment-conjugated nanoparticles induces type I-interferon response and apoptosis

Cancer-Testis Antigens in Triple-Negative Breast Cancer: Role and Potential Utility in Clinical Practice

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