Evaluation of SPP1/osteopontin expression as predictor of recurrence in tamoxifen treated breast cancer

Abstract

Breast cancer patients treated with tamoxifen may experience recurrence due to endocrine resistance, which highlights the need for additional predictive and prognostic biomarkers. The glyco-phosphoprotein osteopontin (OPN), encoded by the SPP1 gene, has previously shown to be associated with poor prognosis in breast cancer. However, studies on the predictive value of OPN are inconclusive. In the present study, we evaluated tissue SPP1 mRNA and OPN protein expression as markers of recurrence in estrogen receptor-positive (ER+) breast cancer tissue. Tamoxifen-treated patients with recurrence or non-recurrence were selected using a matched case-control design. SPP1 mRNA expression was analysed using qPCR (n = 100) and OPN protein by immunohistochemistry (n = 116) using different antibodies. Odds ratios were estimated with conditional logistic regression. The SPP1 expression increased the risk of recurrence with an odds ratio (OR) of 2.50 (95% confidence interval [CI]; 1.30-4.82), after adjustment for tumour grade, HER 2 status and other treatments to OR 3.62 (95% CI; 1.45-9.07). However, OPN protein expression was not associated with risk of recurrence or with SPP1-gene expression, suggesting SPP1 mRNA a stronger prognostic marker candidate compared to tumor tissue OPN protein.Breast cancer is a heterogeneous disease and the majority of tumours express oestrogen receptors (ER). Patients with ER positive (ER+) breast cancer are candidates for endocrine treatment, such as tamoxifen, although up to 30% of women are expected to experience recurrence due to de novo or acquired tamoxifen resistance 1 . Osteopontin (OPN) is a multifunctional secreted integrin-binding glycoprotein, which has been suggested to have a prognostic value and to be involved in the tamoxifen response 2 . The protein is encoded by the secreted phosphoprotein 1 (SPP1) gene, located on chromosome 4 (4q13). As the SPP1 gene transcript is subject to alternative splicing and the OPN protein to post-translational modifications such as proteolytic processing, glycosylation, tyrosine sulfation and serine/threonine phosphorylation, OPN occurs in several variants. The intracellular variant (iOPN) lacks the N-terminal signal sequence and remains in the cytoplasm. The secreted OPN variants (sOPN) include OPN-a, the full-length protein with a total of 7 exons, and the two splice variants OPN-b and OPN-c, lacking exon 5 (aa 59-72) and 4 (aa 31-57) respectively 3 (Fig. 1). Cleavage by proteases (e.g. thrombin, MMP3 and/or MMP7) produces OPN-N (N-terminal fragment) and OPN-C (C-terminal fragment) 4 . The OPN functions are linked to various physiological and pathological events. Several studies have shown a role of OPN in carcinogenesis, mostly by supporting migratory behaviour in tumour cells and regulating the tumour microenvironment in favour of metastasis 5-9 . In addition, OPN promotes epithelial-mesenchymal transition during metastasis, further indicating an important role in cancer progression 10,11 . The clinical utility is recognized in the CancerSeek test...

Comparative transcriptional profiling of canine acanthomatous ameloblastoma and homology with human ameloblastoma

“…Not surprisingly, SPP1 was differentially overexpressed in COSCC compared to CAA, underscoring known differences in biologic behavior 5 . In line with several studies that have investigated the expression levels of SPP1 and OPN in different types of cancer in people 65 , 67 , 68 , these findings might support the use of SPP1 or OPN expression as prognostic biomarkers in CAA and COSCC.…”

Ribosome Proteins Represented by RPL27A Mark the Development and Metastasis of Triple-Negative Breast Cancer in Mouse and Human

“…Lalba is reported to not be expressed in healthy tissues except during lactation, while it is expressed at high levels in a subset of human breast cancers, especially TNBC ( Tuohy, 2014 ). Higher SPP1 gene expression in primary tumors was found to be associated with risk of recurrence in ER + breast cancer among patients with endocrine treatment ( Gothlin Eremo et al, 2020 ). Modification of Sumo2 was associated with the progression and metastasis of breast cancer ( Subramonian et al, 2014 ).…”

TBC1D9: An Important Modulator of Tumorigenesis in Breast Cancer

“…We also observed an increase in SPP1, STAT3, HK2, and HIF-1α in TBC1D9 KD luminal A and TNBC cell lines. SPP1 has a role in tumor progression [44], in metastasis in BC [45], and in recurrence in ER-positive BC [46]. STAT3 is a transcription factor and regulates various aspects of BC, such as cancer onset, progression, proliferation, metastasis, and chemoresistance [47][48][49][50].…”