Cooperative oncogenic effect and cell signaling crosstalk of co‑occurring HER2 and mutant PIK3CA in mammary epithelial cells

  • Authors:
    • Lun Dong
    • Fanyan Meng
    • Ling Wu
    • Allison V. Mitchell
    • C. James Block
    • Bin Zhang
    • Douglas B. Craig
    • Hyejeong Jang
    • Wei Chen
    • Qifeng Yang
    • Guojun Wu
  • View Affiliations

  • Published online on: August 30, 2017     https://doi.org/10.3892/ijo.2017.4108
  • Pages: 1320-1330
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Abstract

Though incidence of PI3K oncogenic mutation is prominent in breast cancer (20-30%), pharmacological targeting of this signaling pathway alone has failed to provide meaningful clinical benefit. To better understand and address this problem, we conducted genome-wide analysis to study the association of mutant PI3K with other gene amplification events. One of the most significant copy number gain events associated with PIK3CA mutation was the region within chromosome 17 containing HER2. To investigate the oncogenic effect and cell signaling regulation of co-occurring PIK3CA-H1047R and or HER2 gene, we generated cell models ectopically expressing mutant PIK3CA, HER2 or both genetic alterations. We observed that cells with both genetic alterations demonstrate increased aggressiveness and invasive capabilities than cells with either genetic change alone. Furthermore, we found that the combination of the HER2 inhibitor (CP-724714) and pan PI3K inhibitor (LY294002) is more potent than either inhibitor alone in terms of inhibition of cell proliferation and colony formation. Significantly, four cell signaling pathways were found in common for cells with HER2, mutant PIK3CA and cells with both genetic alterations through an Affymetric microarray analysis. Moreover, the cells with both genetic alterations acquired more significant replication stress as shown by enriched signaling pathways of cell cycle checkpoint control and DNA damage response signaling. Our study suggests co-occurrence of oncogenic HER2 and mutant PIK3CA cooperatively drives breast cancer progression. The cells with both genetic alterations obtain additional features of replication stress which could open new opportunity for cancer diagnostics and treatment.
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October-2017
Volume 51 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Dong L, Meng F, Wu L, Mitchell AV, Block CJ, Zhang B, Craig DB, Jang H, Chen W, Yang Q, Yang Q, et al: Cooperative oncogenic effect and cell signaling crosstalk of co‑occurring HER2 and mutant PIK3CA in mammary epithelial cells. Int J Oncol 51: 1320-1330, 2017
APA
Dong, L., Meng, F., Wu, L., Mitchell, A.V., Block, C.J., Zhang, B. ... Wu, G. (2017). Cooperative oncogenic effect and cell signaling crosstalk of co‑occurring HER2 and mutant PIK3CA in mammary epithelial cells. International Journal of Oncology, 51, 1320-1330. https://doi.org/10.3892/ijo.2017.4108
MLA
Dong, L., Meng, F., Wu, L., Mitchell, A. V., Block, C. J., Zhang, B., Craig, D. B., Jang, H., Chen, W., Yang, Q., Wu, G."Cooperative oncogenic effect and cell signaling crosstalk of co‑occurring HER2 and mutant PIK3CA in mammary epithelial cells". International Journal of Oncology 51.4 (2017): 1320-1330.
Chicago
Dong, L., Meng, F., Wu, L., Mitchell, A. V., Block, C. J., Zhang, B., Craig, D. B., Jang, H., Chen, W., Yang, Q., Wu, G."Cooperative oncogenic effect and cell signaling crosstalk of co‑occurring HER2 and mutant PIK3CA in mammary epithelial cells". International Journal of Oncology 51, no. 4 (2017): 1320-1330. https://doi.org/10.3892/ijo.2017.4108