An investigation into the role of human mesoderm induction-early response 1α (hMI-ER1α) in regulating growth of human normal and breast carcinoma cells

Huang, Yu-Huei Ivy (2004) An investigation into the role of human mesoderm induction-early response 1α (hMI-ER1α) in regulating growth of human normal and breast carcinoma cells. Masters thesis, Memorial University of Newfoundland.

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Abstract

Mesoderm induction ~arly response 1 (mi-er 1) was first isolated as a novel fibroblast growth factor (FGF)-inducible immediate-early gene activated during mesoderm induction in Xenopus embryos (Paterno et al., 1997). The human orthologue of mi-er 1 shares 91% similarity to the Xenopus sequence at the amino acid level. Human mi-er 1 was shown to be highly expressed in breast carcinoma cell lines and breast tumours while remaining barely detectable in normal breast cell lines and breast tissue (Paterno et al., 1998). In addition, hMI-ER1 was found to interact with estrogen receptor a (Savicky et al., unpublished data) whose dysregulated expression contributes to breast tumour development. These data suggest that the expression of human MI-ER1 is associated with the neoplastic state in breast cancer. The alternate use of a facultative intron at the 3' end of hmi-er 1 gives rise to two major protein isoforms, hMI-ER1α and hMI-ER1β. Transcripts encoding the~ isoform are predominant in almost all tissues. Interestingly, the potent nuclear hormone receptor interaction motif (LXXLL; L represents leucine and X represents any amino acid) is present only in the C-terminus ofhMI-ERlα and hmi-er1α mRNA is observed mainly in endocrine tissues (Paterno et al., 2002). Sequence analysis also revealed that the only bona fide nuclear localization signal (NLS) is located in the C-terminus of~ isoforms (Paterno et al., 2002), suggesting distinct cellular functions ofhMI-ERlα and β isofonns. With all the conserved, functional protein domains, hMI-ER1 was found to interact with various transcriptional and growth regulatory proteins. Such interactions will be important for modulating cell growth in normal and neoplastic cells. In this study, we investigated the functional role of hMI-ERlα in regulating growth of normal and breast cancer cells. Transient overexpression of hMI-ERlα suppressed growth of normal cell lines, but has no significant effect on three breast carcinoma cell lines. In contrast, blocking hMI-ERlα expression by antisense strategy resulted in growth-inhibitory effects on breast cancer cell lines. And the preliminary data from Hoechst staining suggests that the growth-suppressive function of antisense hMIERlα in breast carcinoma cell lines is not due to induction of apoptosis.

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