Regulation of IMP3 by EGFR signaling and repression by ERβ: implications for triple-negative breast cancer

Abstract

Insulin-like growth factor II (IGF-II) mRNA binding protein 3 (IMP3) is emerging as a useful indicator of the progression and outcome of several cancers. IMP3 expression is associated with triple-negative breast carcinomas (TNBCs), which are aggressive tumors associated with poor outcome. In this study, we addressed the hypothesis that signaling pathways, which are characteristic of TNBCs, impact the expression of IMP3 and that IMP3 contributes to the function of TNBCs. The data obtained reveal that IMP3 expression is repressed specifically by estrogen receptor β (ERβ) and its ligand 3βA-diol but not by ERα. EGF receptor (EGFR) signaling and consequent activation of the MAP kinase pathway induce IMP3 transcription and expression. Interestingly, we discovered that the EGFR promoter contains an imperfect estrogen response element and that ERβ represses EGFR transcription. These data support a mechanism in which ERβ inhibits IMP3 expression indirectly by repressing the EGFR. This mechanism relates to the biology of TNBC, which is characterized by diminished ERβ and increased EGFR expression. We also demonstrate that IMP3 contributes to the migration and invasion of breast carcinoma cells. Given that IMP3 is an mRNA binding protein, we determined that it binds several key mRNAs that could contribute to migration and invasion including CD164 (endolyn) and MMP9. Moreover, expression of these mRNAs is repressed by ERβ and enhanced by EGFR signaling, consistent with our proposed mechanism for the regulation of IMP3 expression in breast cancer cells. Our findings show that IMP3 is an effector of EGFR-mediated migration and invasion and they provide the first indication of how this important mRNA binding protein is regulated in cancer.

Fibroepithelial Tumors of the Breast: Pathologic and Immunohistochemical Features and Molecular Mechanisms

“…In breast cancer cells, estrogen receptor beta (ERb) appears to function as a transcriptional repressor of IMP3. 41 It is conceivable that epigenetic mechanisms at the IMP3 promoter might also play a role in its transcriptional reactivation, given that the IMP3 promoter possesses a CpG island that is potentially a target for DNA demethylases and/or histone modification enzymes. Interestingly, IGFBP3 (not to be confused with IGF2BP3 or IMP3), one member of the IGFBP family with an opposite effect on cell growth compared with IMP3, also has a CpG island at its promoter.…”

“…43 Interestingly, more recent data show that epidermal growth factor receptor (EGFR) signaling can induce IMP3 expression, suggesting a complex regulatory pathway of IGF signaling in breast tumorigenesis and progression. 41,44 The molecular mechanisms by which IMP3 is expressed in cancer cells remain unclear. In breast cancer cells, estrogen receptor beta (ERb) appears to function as a transcriptional repressor of IMP3.…”

“…39 Consistent with the notion that reexpression of IMP3 in cancers is important for cancer progression and invasion, knockdown of IMP3 by siRNA is associated with decreased IGF2 protein expression, increased apoptosis, reduced cell migration, and invasion in several cell lines, including cervical carcinoma cell line HeLa and breast cancer cell line MDA-231. 40,41 In the past decade, many studies have demonstrated that IMP3 expression can be used in diagnosis of malignancy and is associated with a poor prognosis for various types of cancers. 42 In breast cancer, our previous study showed that IMP3 may serve as a novel marker for triple-negative breast cancers and is associated with a more aggressive phenotype.…”

Basal-Like Breast Cancer: Update on Clinicopathologic, Immunohistochemical, and Molecular Features

“…Further, we have shown that IMP3 is an effector of EGFR-mediated tumor migration and invasion, which suggests a mechanism by which this mRNA-binding protein may be regulated in cancer. 49 c-kit and p53 c-kit (CD117) is a transmembrane protein that belongs to the family of type III receptor tyrosine kinase. It plays an important role in regulating cell survival, proliferation, and differentiation.…”

Imp3 Expression in Benign and Malignant Thyroid Tumors and Hyperplastic Nodules

“…It is postulated that IMP3 is expressed at low or undetectable levels in mature tissues, except for the placenta (8). However, the expression of IMP3 was reported in tumors of many organs such as the kidney (13), liver (14), endometrium (15), cervix (16), ovary (17), breast (18)(19), pancreas (20), stomach (21), colon (22), bladder (23), and lung (24), as well as in malignant melanoma (25) and some sarcomas (26)(27). Since IMP3 is detected in fetal and neonatal tissues and various tumors, it is considered an oncofetal protein.…”