Osteopontin splice variants are differential predictors of breast cancer treatment responses

Zduniak, Krzysztof; Agrawal, Anil Kumar; Agrawal, Siddarth; Hossain, Monir; Ziółkowski, Piotr; Weber, Georg F.

doi:10.1186/s12885-016-2484-x

Cited by 24 publications

(13 citation statements)

References 18 publications

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“…A major limitation of our study is that this is a retrospective study; our results should therefore be confirmed in validation cohorts, applying the OPN mRNA cut-off used the present study. In addition, protein expression of OPN splice variants should also be evaluated by immunohistochemistry, as suggested in a recent study by Zduniak et al [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

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Association of osteopontin with specific prognostic factors and survival in adjuvant breast cancer trials of the Hellenic Cooperative Oncology Group

Psyrri

Kalogeras

Wirtz³

et al. 2017

J Transl Med

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BackgroundThe shift towards an earlier diagnosis of breast cancer (BC) highlights the need for biomarkers that would identify patients at risk for relapse and metastatic spread and indicate the potential value of additional treatment strategies. Osteopontin (OPN) is a matricellular protein that has been suggested to be a potential biomarker in BC. In the present study, we used archived BC patient samples to assess the clinical utility of OPN.Methods Formalin-fixed paraffin-embedded tumor tissue samples from 975 patients were collected from two large phase III randomized adjuvant chemotherapy trials (HE10/97 and HE10/00) that included patients with high risk BC. All tissue samples were assessed for ER, PgR, Ki67 and HER2 protein expression. OPN protein and mRNA expression was evaluated using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction, respectively.ResultsOPN mRNA expression data were available for 814 patients, whereas OPN protein expression data were available for 546 patients. The majority of patients were ER/PgR-positive (78.3%), HER2-negative (76.5%) and Ki67-positive (55.2%) and had received adjuvant radiation therapy (76.8%) and hormonal therapy (81.1%). OPN mRNA expression was significantly associated with age (60.9% in high OPN tumors vs. 54.1% in low OPN tumors, p = 0.047), ER/PgR-negative status (25.7 vs. 17.2%, p = 0.004) and BC subtypes (p = 0.021). In addition, high OPN mRNA expression was significantly associated with reduced DFS (HR 1.26, 95% CI 1.00–1.59, Wald’s p = 0.050) and OS (HR 1.37, 95% CI 1.05–1.78, p = 0.019), while it retained its prognostic significance for both DFS (HR 1.39, 95% CI 1.10–1.77, p = 0.007) and OS (HR 1.54, 95% CI 1.61–2.05, p = 0.003) in the multivariate analysis.ConclusionsWe showed that high OPN mRNA expression is associated with decreased DFS and OS in a large cohort of BC patients treated with adjuvant chemotherapy in a clinical trial setting. Our results suggest that OPN may serve as a prognostic factor and a potential target for therapy. Trial registration Australian New Zealand Clinical Trials Registry; HE10/97 ACTRN12611000506998; HE10/00 ACTRN12609001036202Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1134-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

“…Although OPN is not tumor-specific, its potential as a tumor biomarker has been demonstrated in several malignancies, including breast cancer [ 3 , 4 ]. Elevated OPN expression has been associated with poor survival of cancer patients with different tumor histotypes [ 5 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

Association of osteopontin with specific prognostic factors and survival in adjuvant breast cancer trials of the Hellenic Cooperative Oncology Group

Psyrri

Kalogeras

Wirtz³

et al. 2017

J Transl Med

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“…The variants have distinct pathophysiological functions in cancer progression and convey distinct information on the disease. We have previously investigated the predictive capabilities of splice variants for treatment responses 8 and their prognostic potential for cancerous lesions. 9,10 A prior meta-analysis confirmed pan-Osteopontin to be correlated with premalignant progression in breast and other transformations.…”

Section: Introductionmentioning

confidence: 99%

Breast cancer risk in premalignant lesions: osteopontin splice variants indicate prognosis

et al. 2018

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BackgroundPremalignant breast lesions pose variable risks for transformation, raising the question who should receive treatment to counteract the potential progression to breast cancer. Because the secreted metastasis mediator Osteopontin (OPN) is a marker for breast cancer aggressiveness, its presence in these lesions may reflect progression risk.MethodsBy immunohistochemistry, we analyse the association of Osteopontin variant expression in healthy breasts, hyperplasias, papillomas, and carcinomas in situ from 434 women to assess a) staining for OPN exon 4 (present in OPN-a and OPN-b) or OPN-c in low-risk to high-risk lesions b) correlations between staining and progression (DCIS with invasion, invasive cancer) or survival.ResultsThe markers correlate with risk, and they are prognostic for ensuing invasive disease and survival. About 10% of OPN-c pathology score 0–1 (intensity), vs. 40% of score 3 experience cancer over 5 years. More than 90% of women, who progress, had pathology scores of 2–3 for OPN-c intensity at the time of initial diagnosis. When combining OPN-c and OPN exon 4 staining, all of the low intensity patients are alive after 5 years, whereas women in the high category have a close to 30% chance to die within 5 years. Of patients who succumb, close to 80% had a high combined score at the time of initial diagnosis.ConclusionThe combined information of OPN splice variant immunohistochemistry can provide a foundation for very reliable prognostication and has the potential to aid decision making in the treatment of early breast lesions.

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“…The reactivity of the autoantibodies was consistent with the appearance of splice variants in individual cancers. Breast cancer expresses OPN-a and -c, but not OPN-b (15,19,20). Liver cancer has elevated levels of OPN-a and -b, but not -c (14).…”

Section: Discussionmentioning

confidence: 99%

Anti‑osteopontin autoantibodies in various types of cancer

Alsarkhi

Weber

2018

Oncol Rep

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The aberrant processing of biomolecules by cancer cells may give rise to autoimmune phenomena. The metastasis gene osteopontin is alternatively spliced only in transformed cells, and the variants promote tumor progression. They may also serve as tumor-associated antigens, and their neutralization by autoantibodies could favorably affect prognosis. A competitive solid-phase ELISA format was applied to determine reactivity toward recombinant osteopontin in human serum or plasma samples. Approximately 35% of thyroid cancer patients and 15% of other cancer patients were found to harbor autoantibodies directed to osteopontin variants, averaging 21% of patients across all cancers studied. The reactivity of the autoantibodies was consistent with the differential appearance of splice variants in individual malignancies. In thyroid cancer, autoantibodies were found to be more frequently associated with a milder form of the disease. The junctions of osteopontin splice variants produced by cancers represent tumor-associated neo-epitopes. Whereas the uniqueness of their sequences renders the acquisition of tolerance during immune maturation improbable, their immunogenicity is predicted to be low. The rare occurrence of antibodies to either osteopontin-b or osteopontin-c suggests that the breaking of tolerance to full-length osteopontin is more prevalent in tumor autoimmunity than a reaction to a poorly immunogenic neo-epitope.

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Osteopontin splice variants are differential predictors of breast cancer treatment responses

Cited by 24 publications

References 18 publications

Association of osteopontin with specific prognostic factors and survival in adjuvant breast cancer trials of the Hellenic Cooperative Oncology Group

Association of osteopontin with specific prognostic factors and survival in adjuvant breast cancer trials of the Hellenic Cooperative Oncology Group

Breast cancer risk in premalignant lesions: osteopontin splice variants indicate prognosis

Anti‑osteopontin autoantibodies in various types of cancer

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