Stathmin 1, a marker of PI3K pathway activation and regulator of microtubule dynamics, is expressed in early pelvic serous carcinomas

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Gynecologic Oncology (Impact Factor: 3.77). 06/2011; 123(1):5-12. DOI: 10.1016/j.ygyno.2011.05.021
Source: PubMed


Most high-grade pelvic serous carcinomas (HGPSCs) arise from fallopian tube epithelium (FTE). To date, few markers have been shown to characterize FTE transformation. Stathmin 1 (STMN1) is a candidate oncogene whose activity is influenced by p53, p27Kip1 (p27), and PI3K/Akt pathway activation. As a microtubule destabilizing protein, STMN1 regulates cytoskeletal dynamics, cell cycle progression, mitosis, and cell migration. This study examines the expression of STMN1 and its negative regulator p27 along the morphologic continuum from normal FTE to invasive carcinoma.
STMN1 and p27 expression were examined by immunohistochemistry (IHC) in benign (n=12) and malignant (n=13) fallopian tubes containing normal epithelium, morphologically benign putative precursor lesions ("p53 signatures"), potential transitional precursor lesions ("proliferative p53 signatures"), tubal intraepithelial carcinoma (TIC), and/or invasive serous carcinoma. STMN1 expression was further assessed in 131 late-stage HGPSCs diagnosed as primary ovarian and in 6 ovarian cancer cell lines by IHC and Western blot, respectively.
STMN1 expression was absent in benign FTE and infrequently detected in p53 signatures. However, it was weakly expressed in proliferative p53 signatures and robustly induced upon progression to TIC and invasive carcinoma, typically accompanied by decreased p27 levels. STMN1 was expressed in >80% of high-grade serous ovarian carcinomas and cell lines.
STMN1 is a novel marker of early serous carcinoma that may play a role in FTE tumor initiation. Our data are consistent with a model by which STMN1 overexpression, resulting from loss of p27-mediated regulation, may potentiate aberrant cell proliferation, migration, and/or loss of polarity during early tumorigenesis.

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Available from: Michelle S Hirsch, Mar 25, 2014
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    • "The findings of this study support that STMN1 and p16, two proteins previously, yet independently, shown to be upregulated in p53-positive early and advanced serous carcinoma [13] [16] [17] [22] [23], are overexpressed in the majority of p53-positive and p53-negative STICs, and in concomitant invasive carcinomas. In this study, 84% of STICs and 96% of invasive carcinomas were positive for STMN1, compared to 100% of positive STICs and invasive carcinomas evaluated in a prior study [16]. In contrast, Sehdev and colleagues reported diffuse p16 immunoreactivity in only 55% (18/33) of STICs [17], which is lower than the 87% observed in this study. "
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    ABSTRACT: . To credential Stathmin 1 (STMN1) and p16(INK4A) (p16) as adjunct markers for the diagnosis of serous tubal intraepithelial carcinoma (STIC), and to compare STMN1 and p16 expression in p53-positive and p53-negative STIC and invasive high-grade serous carcinoma (HGSC). . Immunohistochemistry (IHC) was used to examine STMN1 and p16 expression in fallopian tube specimens (n=31) containing p53-positive and p53-negative STICs, invasive HGSCs, and morphologically normal FTE (fallopian tube epithelium). STMN1 and p16 expression was scored semiquantitatively by four individuals. The semiquantitative scores were dichotomized, and reported as positive or negative. Pooled siRNA was used to knockdown p53 in a panel of cell lines derived from immortalized FTE and HGSC. . STMN1 and p16 were expressed in the majority of p53-positive and p53-negative STICs and concomitant invasive HGSCs, but only scattered positive cells were positive in morphologically normal FTE. Both proteins were expressed consistently across multiple STICs from the same patient and in concomitant invasive HGSC. Knockdown of p53 in immortalized FTE cells and in four HGSC-derived cell lines expressing different missense p53 mutations did not affect STMN1 protein levels. This study demonstrates that STMN1 and p16 are sensitive and specific adjunct biomarkers that, when used with p53 and Ki-67, improve the diagnostic accuracy of STIC. The addition of STMN1 and p16 helps to compensate for practical limitations of p53 and Ki-67 that complicate the diagnosis in up to one third of STICs. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · Gynecologic Oncology
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    • "Importantly, STICs are found not only in BRCA mutation carriers, but are also detected in about 60% of sporadic HGSC (19, 56). STICs are thought to have progressed from the p53 signature and are characterized as being highly proliferative (>10% Ki67) (57), show loss of apical to basal nuclear polarity and, in common with HGSC, demonstrate: over-expression of cyclin-E (58), amplification of hTERT (59), p16 over-expression (CDKN2A), loss of Retinoblastoma protein (Rb) (60), and up-regulation of the PI3K pathway (61) (Figure 1C). In mutation carriers undergoing RRSO, STICs were identified in at least 8% of cases, a higher frequency than seen in patients at low genetic risk (51, 52, 62, 63). "
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    ABSTRACT: Women who have an inherited mutation in the BRCA1 or BRCA2 genes have a substantial increased lifetime risk of developing epithelial ovarian cancer (EOC), and epidemiological factors related to parity, ovulation, and hormone regulation have a dramatic effect on the risk in both BRCA mutation carriers and non-carriers. The most common and most aggressive histotype of EOC, high-grade serous carcinoma (HGSC), is also the histotype associated with germline BRCA mutations. In recent years, evidence has emerged indicating that the likely tissue of origin of HGSC is the fallopian tube. We have reviewed, what is known about the fallopian tube in BRCA mutation carriers at both the transcriptional and translational aspect of their biology. We propose that changes of the transcriptome in BRCA heterozygotes reflect an altered response to the ovulatory stresses from the microenvironment, which may include the post-ovulation inflammatory response and altered reproductive hormone physiology.
    Full-text · Article · Jan 2014 · Frontiers in Oncology
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    • "Stathmin may also be essential for cancer cell survival [23]. More recently, stathmin has been shown to associate with PI3K activity in ovarian cancer [24], supporting the hypothesis that stathmin may be linked to the progression of ovarian cancer. In a previous study, we reported stathmin knockdown to inhibit the activation of Akt and HIF-1í µí»¼ in human endometrial and endothelial cells [25]; however, there is no study on the involvement of the PI3K/Akt/mTOR pathway and stathmin in HIF expression during hypoxia in cultured CCA cells. "
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    ABSTRACT: Stathmin, a microtubule-destabilizing phosphoprotein, is highly expressed in ovarian cancer, but the pathophysiological significance of this protein in ovarian carcinoma cells remains poorly understood. This study reports the involvement of stathmin in the mTOR/HIF-1 α /VEGF pathway in ovarian clear cell adenocarcinoma (CCA) during hypoxia. HIF-1 α protein and VEGF mRNA levels were markedly elevated in RMG-1 cells, a CCA cell line, cultured under hypoxic conditions. Rapamycin, an inhibitor of mTOR complex 1, reduced the level of HIF-1 α and blocked phosphorylation of ribosomal protein S6 kinase 1 (S6K), a transcriptional regulator of mTOR, demonstrating that hypoxia activates mTOR/S6K/HIF-1 α signaling in CCA. Furthermore, stathmin knockdown inhibited hypoxia-induced HIF-1 α and VEGF expression and S6K phosphorylation. The silencing of stathmin expression also reduced Akt phosphorylation, a critical event in the mTOR/HIF-1 α /VEGF signaling pathway. By contrast, stathmin overexpression upregulated hypoxia-induced HIF-1 α and VEGF expression in OVCAR-3 cells, another CCA cell line. In addition, suppression of Akt activation by wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, decreased HIF-1 α and VEGF expression. These results illustrate that regulation of HIF-1 α through the PI3K/Akt/mTOR pathway is controlled by stathmin in CCA. Our findings point to a new mechanism of stathmin regulation during ovarian cancer.
    Full-text · Article · May 2013
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