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Silencing of CXCR4 sensitizes triple-negative breast cancer cells to cisplatin.

Liang S, Peng X, Li X, Yang P, Xie L, Li Y, Du C, Zhang G - Oncotarget (2015)

Bottom Line: We found that CXCR4 silencing significantly inhibited cell growth, decreased colony formation, and enhanced cisplatin sensitivity while overexpression of CXCR4 rendered cells more resistant to cisplatin.Moreover, the percentage of apoptosis and cell cycle arrest at the G2/M phase of cisplatin-treated CXCR4 knockdown cells was significantly higher than control cells.However overexpression of CXCR4 had the reverse effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, PR China.

ABSTRACT
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer for which there is no effective treatment. Previously, we and others demonstrated that CXCR4 surface expression is an independent prognostic factor for disease relapse and survival in breast cancer. In this study, we investigated the effects of CXCR4 gene silencing on cisplatin chemosensitivity in human triple-negative breast cancer cell lines. We found that CXCR4 silencing significantly inhibited cell growth, decreased colony formation, and enhanced cisplatin sensitivity while overexpression of CXCR4 rendered cells more resistant to cisplatin. Moreover, the percentage of apoptosis and cell cycle arrest at the G2/M phase of cisplatin-treated CXCR4 knockdown cells was significantly higher than control cells. Furthermore, we demonstrated CXCR4 knockdown cells showed lower levels of mutant p53 and Bcl-2 protein than the control group, while also having higher levels of caspase-3 and Bax. However overexpression of CXCR4 had the reverse effect. In vivo experiments confirmed that downregulation of CXCR4 enhanced cisplatin anticancer activity in tumor-bearing mice, and that this enhanced anticancer activity is attributable to tumor cell apoptosis. Thus, this study indicates that CXCR4 can modulate cisplatin sensitivity in TNBC cells and suggests that CXCR4 may be a therapeutic target for TNBC.

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CXCR4 knockdown sensitizes TNBC to cisplatin in vivo(A) Gross appearance. Gross appearance and the primary tumors of each group are shown. (B) Growth curves of tumors for MDA-MB-231-NC and MDA-MB-231-shCXCR4 with cisplatin or 0.9% saline. (C) Immunohistochemical staining of xenograft tumors for PCNA (magnification = 40×). (D) Representative pictures of TUNEL-positive staining (brown) for MDA-MB-231-NC and MDA-MB-231-shCXCR4 xenografts. Apoptosis index was calculated as the number of apoptotic cells divided by the total number of tumor cells. *p < 0.05, **p < 0.01, as compared with untreated cells.
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Figure 3: CXCR4 knockdown sensitizes TNBC to cisplatin in vivo(A) Gross appearance. Gross appearance and the primary tumors of each group are shown. (B) Growth curves of tumors for MDA-MB-231-NC and MDA-MB-231-shCXCR4 with cisplatin or 0.9% saline. (C) Immunohistochemical staining of xenograft tumors for PCNA (magnification = 40×). (D) Representative pictures of TUNEL-positive staining (brown) for MDA-MB-231-NC and MDA-MB-231-shCXCR4 xenografts. Apoptosis index was calculated as the number of apoptotic cells divided by the total number of tumor cells. *p < 0.05, **p < 0.01, as compared with untreated cells.

Mentions: We further analyzed whether a similar phenomenon could be observed in vivo using an immunodeficient nude mouse model (Figure 3A). We found that tumors derived from MDA-MB-231-shCXCR4 cells showed slower growth and smaller tumor volume and weight 28 days after implantation, compared to tumors derived from MDA-MB-231 cells. MDA-MB-231-shCXCR4-injected mice that were treated with cisplatin displayed a 6-fold decrease in tumor weight after 4 weeks, compared with the untreated group (p = 0.02; Figure 3B). Furthermore, subcutaneous tumors from MDA-MB-231-injected mice showed increased cell proliferation as indicated by the strong positive staining of PCNA, a marker for cell proliferation, compared with MDA-MB-231-shCXCR4 mice and mice treated with cisplatin (Figure 3C a–d).


Silencing of CXCR4 sensitizes triple-negative breast cancer cells to cisplatin.

Liang S, Peng X, Li X, Yang P, Xie L, Li Y, Du C, Zhang G - Oncotarget (2015)

CXCR4 knockdown sensitizes TNBC to cisplatin in vivo(A) Gross appearance. Gross appearance and the primary tumors of each group are shown. (B) Growth curves of tumors for MDA-MB-231-NC and MDA-MB-231-shCXCR4 with cisplatin or 0.9% saline. (C) Immunohistochemical staining of xenograft tumors for PCNA (magnification = 40×). (D) Representative pictures of TUNEL-positive staining (brown) for MDA-MB-231-NC and MDA-MB-231-shCXCR4 xenografts. Apoptosis index was calculated as the number of apoptotic cells divided by the total number of tumor cells. *p < 0.05, **p < 0.01, as compared with untreated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359214&req=5

Figure 3: CXCR4 knockdown sensitizes TNBC to cisplatin in vivo(A) Gross appearance. Gross appearance and the primary tumors of each group are shown. (B) Growth curves of tumors for MDA-MB-231-NC and MDA-MB-231-shCXCR4 with cisplatin or 0.9% saline. (C) Immunohistochemical staining of xenograft tumors for PCNA (magnification = 40×). (D) Representative pictures of TUNEL-positive staining (brown) for MDA-MB-231-NC and MDA-MB-231-shCXCR4 xenografts. Apoptosis index was calculated as the number of apoptotic cells divided by the total number of tumor cells. *p < 0.05, **p < 0.01, as compared with untreated cells.
Mentions: We further analyzed whether a similar phenomenon could be observed in vivo using an immunodeficient nude mouse model (Figure 3A). We found that tumors derived from MDA-MB-231-shCXCR4 cells showed slower growth and smaller tumor volume and weight 28 days after implantation, compared to tumors derived from MDA-MB-231 cells. MDA-MB-231-shCXCR4-injected mice that were treated with cisplatin displayed a 6-fold decrease in tumor weight after 4 weeks, compared with the untreated group (p = 0.02; Figure 3B). Furthermore, subcutaneous tumors from MDA-MB-231-injected mice showed increased cell proliferation as indicated by the strong positive staining of PCNA, a marker for cell proliferation, compared with MDA-MB-231-shCXCR4 mice and mice treated with cisplatin (Figure 3C a–d).

Bottom Line: We found that CXCR4 silencing significantly inhibited cell growth, decreased colony formation, and enhanced cisplatin sensitivity while overexpression of CXCR4 rendered cells more resistant to cisplatin.Moreover, the percentage of apoptosis and cell cycle arrest at the G2/M phase of cisplatin-treated CXCR4 knockdown cells was significantly higher than control cells.However overexpression of CXCR4 had the reverse effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, PR China.

ABSTRACT
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer for which there is no effective treatment. Previously, we and others demonstrated that CXCR4 surface expression is an independent prognostic factor for disease relapse and survival in breast cancer. In this study, we investigated the effects of CXCR4 gene silencing on cisplatin chemosensitivity in human triple-negative breast cancer cell lines. We found that CXCR4 silencing significantly inhibited cell growth, decreased colony formation, and enhanced cisplatin sensitivity while overexpression of CXCR4 rendered cells more resistant to cisplatin. Moreover, the percentage of apoptosis and cell cycle arrest at the G2/M phase of cisplatin-treated CXCR4 knockdown cells was significantly higher than control cells. Furthermore, we demonstrated CXCR4 knockdown cells showed lower levels of mutant p53 and Bcl-2 protein than the control group, while also having higher levels of caspase-3 and Bax. However overexpression of CXCR4 had the reverse effect. In vivo experiments confirmed that downregulation of CXCR4 enhanced cisplatin anticancer activity in tumor-bearing mice, and that this enhanced anticancer activity is attributable to tumor cell apoptosis. Thus, this study indicates that CXCR4 can modulate cisplatin sensitivity in TNBC cells and suggests that CXCR4 may be a therapeutic target for TNBC.

Show MeSH
Related in: MedlinePlus