Erbb2, foxm1 and 14-3-3ζ prime breast cancer cells for invasion in response to ionizing radiation

ABSTRACT ErbB2 is frequently highly expressed in premalignant breast cancers, including ductal carcinoma _in situ_ (DCIS); however, little is known about the signals or pathways it

contributes to progression into the invasive/malignant state. Radiotherapy is often used to treat early premalignant lesions regardless of ErbB2 status. Here, we show that clinically

relevant doses of ionizing radiation (IR)-induce cellular invasion of ErbB2-expressing breast cancer cells, as well as MCF10A cells overexpressing ErbB2. ErbB2-negative breast cancer cells,

such as MCF7 and T47D, do not invade following treatment with IR nor do MCF10A cells overexpressing epidermal growth factor receptor. ErbB2 becomes phosphorylated at tyrosine 877 in a dose-

and time- dependent manner following exposure to X-rays, and activates downstream signaling cascades including PI3K/Akt. Inhibition of these pathways, as well as inhibition of reactive

oxygen species (ROS) with antioxidants, prevents IR-induced invasion. Activation of ErbB2-dependent signaling results in upregulation of the forkhead family transcription factor, FoxM1, and

its transcriptional targets, including matrix metalloproteinase 2 (MMP2). Inhibition of FoxM1 by RNA interference prevented induction of invasion by IR, and overexpression of FoxM1 in MCF10A

cells was sufficient to promote IR-induced invasion. Moreover, we found that 14-3-3ζ is also upregulated by IR in cancer cells in a ROS-dependent manner, is required for IR-induced invasion

in ErbB2-positive breast cancer cells and together with FoxM1 is sufficient for invasion in ErbB2-negative breast cancer cells. Thus, our data show that IR-mediated activation of ErbB2 and

induction of 14-3-3ζ collaborate to regulate FoxM1 and promote invasion of breast cancer cells and furthermore, may serve as therapeutic targets to enhance radiosensitivity of breast

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support SIMILAR CONTENT BEING VIEWED BY OTHERS ERBB2/HER2-DEPENDENT DOWNREGULATION OF A CELL DEATH-PROMOTING PROTEIN BLNK IN BREAST CANCER CELLS IS REQUIRED FOR 3D BREAST TUMOR GROWTH

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Article Open access 27 September 2022 NUCLEAR ISOFORM OF RAPH1 INTERACTS WITH FOXQ1 TO PROMOTE AGGRESSIVENESS AND RADIORESISTANCE IN BREAST CANCER Article Open access 07 December 2023

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2965–2978. Article  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Gieira Jones and Prachi Thanawala for technical support and Dr Gianluca Gallo for the PI3K activating

peptide. We would also like to thank Drs Jay Reiff and Jacqueline Emrich and the Radiation Oncology Department at Hahnemann University Hospital for their assistance. This work was supported

by Drexel University College of Medicine CURE grants (to MJR). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Biochemistry and Molecular Biology, Drexel University College of

Medicine, Philadelphia, PA, USA D M Kambach, V L Sodi, J Azizkhan-Clifford & M J Reginato * School of Biomedical Engineering, Drexel University, Philadelphia, PA, USA P I Lelkes Authors

* D M Kambach View author publications You can also search for this author inPubMed Google Scholar * V L Sodi View author publications You can also search for this author inPubMed Google

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Reginato. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies the paper on the Oncogene website

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al._ ErbB2, FoxM1 and 14-3-3ζ prime breast cancer cells for invasion in response to ionizing radiation. _Oncogene_ 33, 589–598 (2014). https://doi.org/10.1038/onc.2012.629 Download citation

* Received: 02 July 2012 * Revised: 13 November 2012 * Accepted: 17 November 2012 * Published: 14 January 2013 * Issue Date: 30 January 2014 * DOI: https://doi.org/10.1038/onc.2012.629 SHARE

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clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * ErbB2 * FoxM1 * 14-3-3ζ * invasion * reactive oxygen species