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The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation.

Luo ML, Gong C, Chen CH, Hu H, Huang P, Zheng M, Yao Y, Wei S, Wulf G, Lieberman J, Zhou XZ, Song E, Lu KP - Cell Rep (2015)

Bottom Line: Mechanistically, Rab2A directly interacts with and prevents dephosphorylation/inactivation of Erk1/2 by the MKP3 phosphatase, resulting in Zeb1 upregulation and β-catenin nuclear translocation.Finally, Rab2A overexpression correlates with poor clinical outcome in breast cancer patients.Thus, Pin1/Rab2A/Erk drives BCSC expansion and tumorigenicity, suggesting potential drug targets.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.

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Rab2A Expression Correlates with Pin1 and ALDH1 Expression and with Poor Clinical Outcome in Breast Cancer Patients(A–C) Rab2A expression correlated with Pin1 and ALDH1 expression in the tissue array of normal and cancerous breast tissue.(D) High Rab2A expression correlated with poor overall survival in the tissue array dataset of breast cancer patients.(E) Rab2A was a strong and independent biomarker to predict breast cancer specific survival in the Curtis breast cancer dataset by Cox regression analyses.(F) Boxplots of Rab2A expression stratified by the PAM50 classifier in the Curtis breast cancer dataset.(G) Boxplots of Rab2A expression stratified by the IntClust subtypes in the Curtis breast cancer dataset.(H) Univariate Cox regression analysis showed that HER2-negative, non-triple-negative, or PAM50-normal subtypes of breast cancer patients with higher Rab2A mRNA levels had a higher risk of breast cancer mortality.(I) A schematic model for how the Pin1/Rab2A/Erk signal pathway regulates tumor initiation via CSC regulators, contributing to high mortality in breast cancer. See also Figure S7.
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Figure 7: Rab2A Expression Correlates with Pin1 and ALDH1 Expression and with Poor Clinical Outcome in Breast Cancer Patients(A–C) Rab2A expression correlated with Pin1 and ALDH1 expression in the tissue array of normal and cancerous breast tissue.(D) High Rab2A expression correlated with poor overall survival in the tissue array dataset of breast cancer patients.(E) Rab2A was a strong and independent biomarker to predict breast cancer specific survival in the Curtis breast cancer dataset by Cox regression analyses.(F) Boxplots of Rab2A expression stratified by the PAM50 classifier in the Curtis breast cancer dataset.(G) Boxplots of Rab2A expression stratified by the IntClust subtypes in the Curtis breast cancer dataset.(H) Univariate Cox regression analysis showed that HER2-negative, non-triple-negative, or PAM50-normal subtypes of breast cancer patients with higher Rab2A mRNA levels had a higher risk of breast cancer mortality.(I) A schematic model for how the Pin1/Rab2A/Erk signal pathway regulates tumor initiation via CSC regulators, contributing to high mortality in breast cancer. See also Figure S7.

Mentions: We analyzed expression of Rab2A, Pin1, and ALDH1, a marker for stem and progenitor cells as well as BCSCs (Ginestier et al., 2007), in normal and cancerous breast tissue arrays using immunohistochemistry. Pin1 and Rab2A were undetectable or low in all 24 human normal breast tissue, but their expression was dramatically increased in many of 65 human breast cancer tissue (Figures 7A and 7B). Remarkably, Rab2A expression was highly correlated with Pin1 and ALDH1 expression in normal and cancerous breast tissue (Figures 7A–7C). We next analyzed the correlation of Rab2A expression and clinical outcome in the subset of 52 breast cancer patients, for which clinical data were available. Higher Rab2A expression was significantly associated with higher mortality in breast cancer patients, as shown by Kaplan-Meier survival curves (p = 0.012) (Figure 7D).


The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation.

Luo ML, Gong C, Chen CH, Hu H, Huang P, Zheng M, Yao Y, Wei S, Wulf G, Lieberman J, Zhou XZ, Song E, Lu KP - Cell Rep (2015)

Rab2A Expression Correlates with Pin1 and ALDH1 Expression and with Poor Clinical Outcome in Breast Cancer Patients(A–C) Rab2A expression correlated with Pin1 and ALDH1 expression in the tissue array of normal and cancerous breast tissue.(D) High Rab2A expression correlated with poor overall survival in the tissue array dataset of breast cancer patients.(E) Rab2A was a strong and independent biomarker to predict breast cancer specific survival in the Curtis breast cancer dataset by Cox regression analyses.(F) Boxplots of Rab2A expression stratified by the PAM50 classifier in the Curtis breast cancer dataset.(G) Boxplots of Rab2A expression stratified by the IntClust subtypes in the Curtis breast cancer dataset.(H) Univariate Cox regression analysis showed that HER2-negative, non-triple-negative, or PAM50-normal subtypes of breast cancer patients with higher Rab2A mRNA levels had a higher risk of breast cancer mortality.(I) A schematic model for how the Pin1/Rab2A/Erk signal pathway regulates tumor initiation via CSC regulators, contributing to high mortality in breast cancer. See also Figure S7.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401741&req=5

Figure 7: Rab2A Expression Correlates with Pin1 and ALDH1 Expression and with Poor Clinical Outcome in Breast Cancer Patients(A–C) Rab2A expression correlated with Pin1 and ALDH1 expression in the tissue array of normal and cancerous breast tissue.(D) High Rab2A expression correlated with poor overall survival in the tissue array dataset of breast cancer patients.(E) Rab2A was a strong and independent biomarker to predict breast cancer specific survival in the Curtis breast cancer dataset by Cox regression analyses.(F) Boxplots of Rab2A expression stratified by the PAM50 classifier in the Curtis breast cancer dataset.(G) Boxplots of Rab2A expression stratified by the IntClust subtypes in the Curtis breast cancer dataset.(H) Univariate Cox regression analysis showed that HER2-negative, non-triple-negative, or PAM50-normal subtypes of breast cancer patients with higher Rab2A mRNA levels had a higher risk of breast cancer mortality.(I) A schematic model for how the Pin1/Rab2A/Erk signal pathway regulates tumor initiation via CSC regulators, contributing to high mortality in breast cancer. See also Figure S7.
Mentions: We analyzed expression of Rab2A, Pin1, and ALDH1, a marker for stem and progenitor cells as well as BCSCs (Ginestier et al., 2007), in normal and cancerous breast tissue arrays using immunohistochemistry. Pin1 and Rab2A were undetectable or low in all 24 human normal breast tissue, but their expression was dramatically increased in many of 65 human breast cancer tissue (Figures 7A and 7B). Remarkably, Rab2A expression was highly correlated with Pin1 and ALDH1 expression in normal and cancerous breast tissue (Figures 7A–7C). We next analyzed the correlation of Rab2A expression and clinical outcome in the subset of 52 breast cancer patients, for which clinical data were available. Higher Rab2A expression was significantly associated with higher mortality in breast cancer patients, as shown by Kaplan-Meier survival curves (p = 0.012) (Figure 7D).

Bottom Line: Mechanistically, Rab2A directly interacts with and prevents dephosphorylation/inactivation of Erk1/2 by the MKP3 phosphatase, resulting in Zeb1 upregulation and β-catenin nuclear translocation.Finally, Rab2A overexpression correlates with poor clinical outcome in breast cancer patients.Thus, Pin1/Rab2A/Erk drives BCSC expansion and tumorigenicity, suggesting potential drug targets.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.

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Related in: MedlinePlus