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ErbB2, FoxM1 and 14-3-3? 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 14-3-3? 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 14-3-3? collaborate to regulate FoxM1 and promote invasion of breast cancer cells and furthermore, may serve as therapeutic targets to enhance radiosensitivity of breast cancers.

SUBMITTER: Kambach DM

PROVIDER: S-EPMC3966179 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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ErbB2, FoxM1 and 14-3-3ζ prime breast cancer cells for invasion in response to ionizing radiation.

Kambach D M DM Sodi V L VL Lelkes P I PI Azizkhan-Clifford J J Reginato M J MJ

Oncogene 20130114 5

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 ...[more]

PMID: 23318431

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Project description:IntroductionDespite the benefits of estrogen receptor (ER)-targeted endocrine therapies in breast cancer, many tumors develop resistance. 14-3-3 ζ/YWHAZ, a member of the 14-3-3 family of conserved proteins, is over-expressed in several types of cancer, and our previous work showed that high expression of 14-3-3ζ in ER-positive breast cancers was associated with a poor clinical outcome for women on tamoxifen. Therefore, we now probe the role of 14-3-3ζ in endocrine resistance, and we examine the functional dimensions and molecular basis that underlie 14-3-3ζ activities.MethodsFrom analyses of four independent breast cancer microarray datasets from nearly 400 women, we characterized a gene signature that correlated strongly with high expression of 14-3-3ζ in breast tumors and examined its association with breast cancer molecular subtypes and clinical-pathological features. We investigated the effects of altering 14-3-3ζ levels in ER-positive, endocrine sensitive and resistant breast cancer cells on the regulation of 14-3-3ζ signature genes, and on cellular signaling pathways and cell phenotypic properties.ResultsThe gene signature associated with high 14-3-3ζ levels in breast tumors encompassed many with functions in mitosis and cytokinesis, including aurora kinase-B, polo-like kinase-1, CDC25B, and BIRC5/survivin. The gene signature correlated with early recurrence and risk of metastasis, and was found predominantly in luminal B breast cancers, the more aggressive ER-positive molecular subtype. The expression of the signature genes was significantly decreased or increased upon reduction or overexpression of 14-3-3ζ in ER-positive breast cancer cells, indicating their coregulation. 14-3-3ζ also played a critical role in the regulation of FOXM1, with 14-3-3ζ acting upstream of FOXM1 to regulate cell division-signature genes. Depletion of 14-3-3ζ markedly increased apoptosis, reduced proliferation and receptor tyrosine kinase (HER2 and EGFR) signaling, and, importantly, reversed endocrine resistance.ConclusionsThis study reveals that 14-3-3ζ is a key predictive marker for risk of failure on endocrine therapy and serves a pivotal role impacting growth factor signaling, and promoting cell survival and resistance to endocrine therapies. Targeting 14-3-3ζ and its coregulated proteins, such as FOXM1, should prove valuable in restoring endocrine sensitivity and reducing risk of breast cancer recurrence.

Dataset Information

ErbB2, FoxM1 and 14-3-3? prime breast cancer cells for invasion in response to ionizing radiation.

Publications

ErbB2, FoxM1 and 14-3-3ζ prime breast cancer cells for invasion in response to ionizing radiation.

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