Proliferation marker securin identifies favourable outcome in invasive ductal breast cancer

Department of Pathology, Turku University Hospital, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland.
British Journal of Cancer (Impact Factor: 4.84). 08/2008; 99(2):335-40. DOI: 10.1038/sj.bjc.6604475
Source: PubMed


We introduce a new proliferation marker, securin (pituitary tumour-transforming 1 (PTTG1)), analysed in invasive ductal breast carcinomas by cDNA microarrays and immunohistochemistry. In cDNA microarray of a total of 4000 probes of genes, securin was revealed with a significant change in expression among the several proliferation-related genes studied. The value of securin as a proliferation marker was verified immunohistochemically (n=44) in invasive ductal breast cancer. In follow-up analyses of the sample of patients, the prognostic value of securin was compared with the established markers of breast cancer proliferation, Ki-67 and mitotic activity index (MAI). Our results of a small sample of patients suggest that low securin expression identifies a distinct subgroup of more favourable outcome among patients with high Ki-67 immunoexpression or high MAI. In univariate analysis of Cox's regression, 10-unit increment of securin immunopositivity was associated with a 2.3-fold overall risk of death due to breast cancer and a 7.1-fold risk of death due to breast cancer in the sample of patients stratified according to the cutoff points of 10 and 20% of securin immunopositivity. We suggest that securin immunostaining is a promising and clinically applicable proliferation marker. The finding urges further prognostic studies with a large sample of patients.

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    • "Since in the breast cancer the PTTG1 is showing opposite expression pattern of pathway analogues such as securin [28], its detection could be of great clinical importance, being informative for the tumor proliferative capacity and very likely the simultaneous presence of the p53 oncogene mutation pointing towards worse prognosis, shorter time to relapse, and disease progression. In our group only one patient had low proliferation index being insufficient for the speculation, but the immunoreactivity in the metastatic cells allows us to state the presence of the evidence regarding the coexistence of PTTG1 and more aggressive tumor pheno- types. "
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    ABSTRACT: Despite the advances that have been made in the fields of molecular and cell biology, there is still considerable debate explaining how the breast cancer cells progress through carcinogenesis and acquire their metastatic ability. The lack of preventive methods and effective therapies underlines the pressing need to identify new biomarkers that can aid early diagnosis and may be targets for effective therapeutic strategies. In this study we explore the pituitary tumor-transforming gene 1 (PTTG1) expression in primary ductal breast carcinoma, lymph node infiltration, and distant metastases. Three human cell lines, 184B5 derived from normal mammary epithelium, HCC70 from a primary ductal carcinoma, and MDA-MB-361 from a breast metastasis, were used for quantifying PTTG1 mRNA expression. The PTTG1 immunohistochemical expression was carried out on specimens taken from eight patients with invasive ductal breast cancer who underwent surgical treatment and followup for five years retrospectively selected. The study demonstrated that PTTG1 is expressed gradually in primary ductal breast carcinoma, lymph node infiltration, and distant metastases. Our findings suggest that the immunohistochemical evaluation of PTTG1 expression might be a powerful biomarker of recognition and quantification of the breast cancer cells in routine pathological specimens and a potential target for developing an effective immunotherapeutic strategy for primary and metastatic breast cancer.
    Disease markers 09/2013; 35(4):267-72. DOI:10.1155/2013/912304 · 1.56 Impact Factor
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    • "Increased expression of hPTTG1 has been observed to be associated with poor prognosis in several types of human cancers [4-8]. In breast cancer, hPTTG1 overexpression is a proliferation marker [9] and can be considered a prognostic marker or a molecular signature of metastasis and recurrence [10,11]. "
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    ABSTRACT: Introduction hPTTG1 (human pituitary tumor-transforming gene 1) is an oncogene overexpressed in breast cancer and several other types of cancer. Increased hPTTG1 expression has been shown to be associated with poor patient outcomes in breast cancer. Although hPTTG1 overexpression plays important roles in promoting the proliferation, invasion, and metastasis of cancer cells, it also has been suggested to induce cellular senescence. Deciphering the mechanism by which hPTTG1 overexpression induces these contradictory actions in breast cancer cells is critical to our understanding of the role of hPTTG1 in breast cancer development. Methods MCF-10A and MCF-7 cells were used to identify the mechanism of hPTTG1-induced senescence. The interplay between hPTTG1 overexpression and chemokine C-X-C motif receptor 2 (CXCR2)/p21-dependent senescence in tumor growth and metastasis of MCF-7 cells was investigated by orthotopic transplantation of severe combined immunodeficiency (SCID) mice. Additionally, human invasive ductal carcinoma (IDC) tissue arrays were used to confirm the hPTTG1/CXCR2/p21 axis established in vitro. Results In this study, we investigated the mechanism of hPTTG1-induced senescence as well as its role in breast cancer progression and metastasis. Herein, we showed that hPTTG1 overexpression reinforced senescence through the CXCR2/p21 signaling. Furthermore, hPTTG1 overexpression activated NF-κB signaling to transactivate the expression of interleukin (IL)-8 and growth-regulated oncogene alpha (GROα) to execute CXCR2 signaling in MCF-7 cells. When CXCR2 expression was knocked down in hPTTG1-overexpressing MCF-7 cells, hPTTG1-induced senescence was abrogated by alleviating CXCR2-induced p21 expression. In a mouse model, CXCR2-mediated senescence limited hPTTG1-induced tumor growth and metastasis. Moreover, CXCR2 knockdown in hPTTG1-overexpressing MCF-7 tumors dramatically accelerated tumor growth and metastasis. Our in vitro and in vivo results demonstrated that hPTTG1 overexpression reinforces senescence through CXCR2 signaling, and the evasion of CXCR2/p21-dependent senescence was critical to hPTTG1 exerting its oncogenic potential. Interestingly, although CXCR2-dependent senescence restrained hPTTG1-induced tumor progression, when MCF-7 cells and hPTTG1-overexpressing MCF-7 cells were co-transplanted into the mammary fat pads of SCID mice, hPTTG1-overexpressing senescent cells created a metastasis-promoting microenvironment that promoted lung metastasis of the MCF-7 cells. Immunohistochemical analysis of human breast tumor samples also confirmed the importance of the hPTTG1/CXCR2 axis in promoting breast cancer metastasis. Conclusions Our findings provide novel molecular insights into hPTTG1-induced senescence and identify a novel mechanism by which hPTTG1 promotes metastasis by regulating the senescence-associated microenvironment.
    Breast cancer research: BCR 07/2012; 14(4):R106. DOI:10.1186/bcr3226 · 5.49 Impact Factor
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    • "The observed average level of securin immunopositivity in our present results differs from that of our previous study (Talvinen et al, 2008). The obvious explanations lie in the different patient selection procedure and histological material. "
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    ABSTRACT: Securin is a recently recognised oncogene with multiple known functions in initiation, progression and cell cycle regulation in several malignant diseases, including breast carcinoma. In this paper, the prognostic value of securin is evaluated by immunohistochemistry in 310 patients diagnosed with invasive breast cancer during a mammographic screening programme in Central Finland. All patients were directed to modern surgical and oncological treatments and were followed up for a maximum of 20 years. Our results suggest that securin immunopositivity is an independent prognosticator of invasive breast cancer. In our study, securin predicted breast cancer-specific survival among all cases of invasive breast cancer and subgroups divided according to histological type, Ki-67 proliferation status and tumour size. Especially in a multivariate analysis standardised for axillary lymph node status, patient's age and tumour size at the time of diagnosis, securin immunopositivity indicated a 13.1-fold risk of breast cancer death (P=0.024) among invasive ductal breast carcinomas with low Ki-67 positivity. Our present and previous results suggest that securin could be useful in clinical pathology to intensify the power of the established prognosticators of invasive breast cancer and, especially, to assist in identifying patients with a more favourable outcome than that indicated by Ki-67 alone.
    British Journal of Cancer 09/2009; 101(6):1005-10. DOI:10.1038/sj.bjc.6605237 · 4.84 Impact Factor
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