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Expression of the embryonic stem cell marker SOX2 in early-stage breast carcinoma.

Lengerke C, Fehm T, Kurth R, Neubauer H, Scheble V, Müller F, Schneider F, Petersen K, Wallwiener D, Kanz L, Fend F, Perner S, Bareiss PM, Staebler A - BMC Cancer (2011)

Bottom Line: SOX2 expression was detected across different breast cancer subtypes and did not correlate with tumor grading.However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018).Corresponding metastatic lymph nodes showed higher SOX2 expression and were significantly more often SOX2 positive than primary tumors (p = 0.0432).

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Tuebingen Medical Center II, Otfried-Mueller-Strasse 10, 72076 Tuebingen, Germany. claudia.lengerke@med.uni-tuebingen.de

ABSTRACT

Background: The SRY-related HMG-box family of transcription factors member SOX2 has been mainly studied in embryonic stem cells as well as early foregut and neural development. More recently, SOX2 was shown to participate in reprogramming of adult somatic cells to a pluripotent stem cell state and implicated in tumorigenesis in various organs. In breast cancer, SOX2 expression was reported as a feature of basal-like tumors. In this study, we assessed SOX2 expression in 95 primary tumors of postmenopausal breast cancer patients.

Methods: Samples from 95 patients diagnosed and treated at the University of Tuebingen Institute of Pathology and Women's Hospital were analyzed by immunohistochemistry for SOX2 expression in the primary tumor samples and in corresponding lymph node metastasis, where present. Furthermore, SOX2 amplification status was assessed by FISH in representative samples. In addition, eighteen fresh frozen samples were analyzed for SOX2, NANOG and OCT4 gene expression by real-time PCR.

Results: SOX2 expression was detected in 28% of invasive breast carcinoma as well as in 44% of ductal carcinoma in situ (DCIS) lesions. A score of SOX2 expression (score 0 to 3) was defined in order to distinguish SOX2 negative (score 0) from SOX2 positive samples (score 1-3) and among latter the subgroup of SOX2 high expressors (score 3 > 50% positive cells). Overall, the incidence of SOX2 expression (score 1-3) was higher than previously reported in a cohort of lymph node negative patients (28% versus 16.7%). SOX2 expression was detected across different breast cancer subtypes and did not correlate with tumor grading. However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018). Corresponding metastatic lymph nodes showed higher SOX2 expression and were significantly more often SOX2 positive than primary tumors (p = 0.0432).

Conclusions: In this report, we show that the embryonic stem cell factor SOX2 is expressed in a variety of early stage postmenopausal breast carcinomas and metastatic lymph nodes. Our data suggest that SOX2 plays an early role in breast carcinogenesis and high expression may promote metastatic potential. Further studies are needed to explore whether SOX2 can predict metastatic potential at an early tumor stage.

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Gene expression of SOX2, NANOG and OCT4 in different tumor samples shows clustering of embryonic factors in certain tumors. Real-time PCR for SOX2, NANOG and OCT4 was performed on isolated RNA from tumor tissue. RNA from undifferentiated human pluripotent stem cells was used as a control. Shown are fold relative gene expression levels in comparison to undifferentiated pluripotent stem cells. Experiments have been performed in triplicates: error bars depict standard deviations.
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Figure 3: Gene expression of SOX2, NANOG and OCT4 in different tumor samples shows clustering of embryonic factors in certain tumors. Real-time PCR for SOX2, NANOG and OCT4 was performed on isolated RNA from tumor tissue. RNA from undifferentiated human pluripotent stem cells was used as a control. Shown are fold relative gene expression levels in comparison to undifferentiated pluripotent stem cells. Experiments have been performed in triplicates: error bars depict standard deviations.

Mentions: Eleven SOX2 positive samples (7 belonging to expression score 3 and 4 of score 2), 4 SOX2 negative samples as well as 3 lymph-node samples showing high SOX2 expression (score 3) were analyzed by FISH to explore whether aberrant SOX2 expression is a result of gene amplification as previously reported in other carcinomas [20]. Surprisingly, with the exception of one case of low level amplification documented in a score 3 primary tumor, unlike reported in other tumors, the majority of analyzed samples did not show SOX2 gene amplifications, suggesting that at least in part of the breast carcinomas expressing SOX2, the aberrant gene expression is driven by other mechanisms. To explore whether SOX2 induction is part of a more general reactivation of embryonic genes, we assessed co-expression of NANOG and OCT4 in the same tumors by performing real-time PCR analysis and using human pluripotent stem cells as positive controls [17]. Among fresh frozen samples collected prospectively from n = 18 patients we observed various degrees of SOX2 gene expression (Figure 3), confirming our immunohistochemical data. However, samples showing more pronounced SOX2 expression levels (sample 1, 3 and 10) displayed substantial co-expression of OCT4 and NANOG (Figure 3). Furthermore, co-expression with the previously described SOX interacting gene ALX4 as well as with the SOX2-overlapping transcript (SOX2OT) could be documented in SOX2-expressing samples (Additional file 1, Figure S1) [21,22].


Expression of the embryonic stem cell marker SOX2 in early-stage breast carcinoma.

Lengerke C, Fehm T, Kurth R, Neubauer H, Scheble V, Müller F, Schneider F, Petersen K, Wallwiener D, Kanz L, Fend F, Perner S, Bareiss PM, Staebler A - BMC Cancer (2011)

Gene expression of SOX2, NANOG and OCT4 in different tumor samples shows clustering of embryonic factors in certain tumors. Real-time PCR for SOX2, NANOG and OCT4 was performed on isolated RNA from tumor tissue. RNA from undifferentiated human pluripotent stem cells was used as a control. Shown are fold relative gene expression levels in comparison to undifferentiated pluripotent stem cells. Experiments have been performed in triplicates: error bars depict standard deviations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3038979&req=5

Figure 3: Gene expression of SOX2, NANOG and OCT4 in different tumor samples shows clustering of embryonic factors in certain tumors. Real-time PCR for SOX2, NANOG and OCT4 was performed on isolated RNA from tumor tissue. RNA from undifferentiated human pluripotent stem cells was used as a control. Shown are fold relative gene expression levels in comparison to undifferentiated pluripotent stem cells. Experiments have been performed in triplicates: error bars depict standard deviations.
Mentions: Eleven SOX2 positive samples (7 belonging to expression score 3 and 4 of score 2), 4 SOX2 negative samples as well as 3 lymph-node samples showing high SOX2 expression (score 3) were analyzed by FISH to explore whether aberrant SOX2 expression is a result of gene amplification as previously reported in other carcinomas [20]. Surprisingly, with the exception of one case of low level amplification documented in a score 3 primary tumor, unlike reported in other tumors, the majority of analyzed samples did not show SOX2 gene amplifications, suggesting that at least in part of the breast carcinomas expressing SOX2, the aberrant gene expression is driven by other mechanisms. To explore whether SOX2 induction is part of a more general reactivation of embryonic genes, we assessed co-expression of NANOG and OCT4 in the same tumors by performing real-time PCR analysis and using human pluripotent stem cells as positive controls [17]. Among fresh frozen samples collected prospectively from n = 18 patients we observed various degrees of SOX2 gene expression (Figure 3), confirming our immunohistochemical data. However, samples showing more pronounced SOX2 expression levels (sample 1, 3 and 10) displayed substantial co-expression of OCT4 and NANOG (Figure 3). Furthermore, co-expression with the previously described SOX interacting gene ALX4 as well as with the SOX2-overlapping transcript (SOX2OT) could be documented in SOX2-expressing samples (Additional file 1, Figure S1) [21,22].

Bottom Line: SOX2 expression was detected across different breast cancer subtypes and did not correlate with tumor grading.However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018).Corresponding metastatic lymph nodes showed higher SOX2 expression and were significantly more often SOX2 positive than primary tumors (p = 0.0432).

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Tuebingen Medical Center II, Otfried-Mueller-Strasse 10, 72076 Tuebingen, Germany. claudia.lengerke@med.uni-tuebingen.de

ABSTRACT

Background: The SRY-related HMG-box family of transcription factors member SOX2 has been mainly studied in embryonic stem cells as well as early foregut and neural development. More recently, SOX2 was shown to participate in reprogramming of adult somatic cells to a pluripotent stem cell state and implicated in tumorigenesis in various organs. In breast cancer, SOX2 expression was reported as a feature of basal-like tumors. In this study, we assessed SOX2 expression in 95 primary tumors of postmenopausal breast cancer patients.

Methods: Samples from 95 patients diagnosed and treated at the University of Tuebingen Institute of Pathology and Women's Hospital were analyzed by immunohistochemistry for SOX2 expression in the primary tumor samples and in corresponding lymph node metastasis, where present. Furthermore, SOX2 amplification status was assessed by FISH in representative samples. In addition, eighteen fresh frozen samples were analyzed for SOX2, NANOG and OCT4 gene expression by real-time PCR.

Results: SOX2 expression was detected in 28% of invasive breast carcinoma as well as in 44% of ductal carcinoma in situ (DCIS) lesions. A score of SOX2 expression (score 0 to 3) was defined in order to distinguish SOX2 negative (score 0) from SOX2 positive samples (score 1-3) and among latter the subgroup of SOX2 high expressors (score 3 > 50% positive cells). Overall, the incidence of SOX2 expression (score 1-3) was higher than previously reported in a cohort of lymph node negative patients (28% versus 16.7%). SOX2 expression was detected across different breast cancer subtypes and did not correlate with tumor grading. However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018). Corresponding metastatic lymph nodes showed higher SOX2 expression and were significantly more often SOX2 positive than primary tumors (p = 0.0432).

Conclusions: In this report, we show that the embryonic stem cell factor SOX2 is expressed in a variety of early stage postmenopausal breast carcinomas and metastatic lymph nodes. Our data suggest that SOX2 plays an early role in breast carcinogenesis and high expression may promote metastatic potential. Further studies are needed to explore whether SOX2 can predict metastatic potential at an early tumor stage.

Show MeSH
Related in: MedlinePlus