Abstract
Since the early 1980s remarkable progress has been made in understanding the role of the HER2 locus in carcinogenesis, but many details of its regulatory network are still elusive. We recently reported the finding of 367 new human microRNA (miRNA) genes of which one, mir-4728, is encoded in an intron of the HER2 gene. Here, we confirm that the HER2 oncogene is a bi-functional locus encoding the membrane receptor and a functional miRNA gene. We further show that miR-4728-3p has alternative functionalities depending on the region used for interaction with its target; the canonical seed between nucleotides 2–8 or a novel, more internal seed shifted to nucleotides 6–12. Analysis of public data shows that this internal seed region, although rare compared to the far more abundant canonical 2–8 seed interaction, can also direct targeted down-regulation by other miRNAs. Through the internal seed, miR-4728-3p regulates expression of estrogen receptor alpha, an interaction that would have remained undetected if classic rules for miRNA-target interaction had been applied. In summary, we present here an alternative mode of miRNA regulation and demonstrate this dual function of the HER2 locus, linking the two major biomarkers in breast cancer.
Highlights
Human epidermal growth factor receptor 2 (Erbb2/HER2, hereafter called HER2) and estrogen receptor alpha (ESR1) are the most important prognostic and treatment predictive biomarkers in breast cancer (BC) and they are the most widely used therapeutic targets for this disease [1,2].The HER2 oncogene is amplified in 15–20% of all invasive BCs, leading to overexpression of the gene
MicroRNA-4728-3p uses two different seed interactions In our previous work we showed that the dominant mature form of mir-4728 is the one derived from the 3’ arm of the precursor; miR-4728-3p [7]
We have demonstrated that the HER2 gene is a bi-functional locus
Summary
Human epidermal growth factor receptor 2 (Erbb2/HER2, hereafter called HER2) and estrogen receptor alpha (ESR1) are the most important prognostic and treatment predictive biomarkers in breast cancer (BC) and they are the most widely used therapeutic targets for this disease [1,2].The HER2 oncogene is amplified in 15–20% of all invasive BCs, leading to overexpression of the gene. More than 70% of all BCs overexpress ESR1 as judged by immunohistochemistry (ER+ tumors) and expression of ESR1 is highly predictive of clinical benefit from endocrine therapies such as treatment with estrogen receptor modulators or aromatase inhibitors. HER2 amplification-driven carcinogenesis implies protein overexpression and increased signal transduction, but the basal requirement for transformation is transcriptional overexpression [4]. This may suggest that the oncogenic activity is not solely associated with mitogenic signaling [6]. Simultaneous production of HER2 mRNA and the miRNA implies that this locus may have functions that are independent of signal transduction through the HER2 receptor
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