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Identification and characterization of new miRNAs cloned from normal mouse mammary gland.

ABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that have been found to play important roles in silencing target genes and that are involved in the regulation of various normal cellular processes. Until now their implication in the mammary gland biology was suggested by few studies mainly focusing on pathological situations allowing the characterization of miRNAs as markers of breast cancer tumour classes. If in the normal mammary gland, the expression of known miRNAs has been studied in human and mice but the full repertoire of miRNAs expressed in this tissue is not yet available. RESULTS: To extend the repertoire of mouse mammary gland expressed miRNAs, we have constructed several libraries of small miRNAs allowing the cloning of 455 sequences. After bioinformatics' analysis, 3 known miRNA (present in miRbase) and 33 new miRNAs were identified. Expression of 24 out of the 33 has been confirmed by RT-PCR. Expression of none of them was found to be mammary specific, despite a tissue-restricted distribution of some of them. No correlation could be established between their expression pattern and evolutionary conservation. Six of them appear to be mouse specific. In several cases, multiple potential precursors of miRNA were present in the genome and we have developed a strategy to determine which of them was able to mature the miRNA. CONCLUSION: The cloning approach has allowed improving the repertoire of miRNAs in the mammary gland, an evolutionary recent organ. This tissue is a good candidate to find tissue-specific miRNAs and to detect miRNA specific to mammals. We provide evidence for 24 new miRNA. If none of them is mammary gland specific, a few of them are not ubiquitously expressed. For the first time 6 mouse specific miRNA have been identified.

SUBMITTER: Sdassi N

PROVIDER: S-EPMC2683868 | biostudies-other | 2009

REPOSITORIES: biostudies-other

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Identification and characterization of new miRNAs cloned from normal mouse mammary gland.

Sdassi Nezha N Silveri Licia L Laubier Johann J Tilly Gaëlle G Costa José J Layani Sarah S Vilotte Jean-Luc JL Le Provost Fabienne F

BMC genomics 20090407

<h4>Background</h4>MicroRNAs (miRNAs) are small non-coding RNAs that have been found to play important roles in silencing target genes and that are involved in the regulation of various normal cellular processes. Until now their implication in the mammary gland biology was suggested by few studies mainly focusing on pathological situations allowing the characterization of miRNAs as markers of breast cancer tumour classes. If in the normal mammary gland, the expression of known miRNAs has been st ...[more]

PMID: 19351399

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Project description:BackgroundThe Six1 homeobox gene is highly expressed in the embryonic mammary gland, continues to be expressed in early postnatal mammary development, but is lost when the mammary gland differentiates during pregnancy. However, Six1 is re-expressed in breast cancers, suggesting that its re-instatement in the adult mammary gland may contribute to breast tumorigenesis via initiating a developmental process out of context. Indeed, recent studies demonstrate that Six1 overexpression in the adult mouse mammary gland is sufficient for initiating invasive carcinomas, and that its overexpression in xenograft models of mammary cancer leads to metastasis. These data demonstrate that Six1 is causally involved in both breast tumorigenesis and metastasis, thus raising the possibility that it may be a viable therapeutic target. However, because Six1 is highly expressed in the developing mammary gland, and because it has been implicated in the expansion of mammary stem cells, targeting Six1 as an anti-cancer therapy may have unwanted side effects in the breast.ResultsWe sought to determine the role of Six1 in mammary development using two independent mouse models. To study the effect of Six1 loss in early mammary development when Six1 is normally expressed, Six1-/- embryonic mammary glands were transplanted into Rag1-/- mice. In addition, to determine whether Six1 downregulation is required during later stages of development to allow for proper differentiation, we overexpressed Six1 during adulthood using an inducible, mammary-specific transgenic mouse model. Morphogenesis of the mammary gland occurred normally in animals transplanted with Six1-/- embryonic mammary glands, likely through the redundant functions of other Six family members such as Six2 and Six4, whose expression was increased in response to Six1 loss. Surprisingly, inappropriate expression of Six1 in the adult mammary gland, when levels are normally low to absent, did not inhibit normal mammary differentiation during pregnancy or lactation.ConclusionsSix1 is not critical for normal mammary gland development, since neither loss nor inappropriate overexpression of Six1 adversely affects normal mammary gland development or function. However, as both Six2 and Six4 levels are increased in Six1-/- mammary glands, we postulate that these Six family members are functionally redundant in the gland, as is true of many homeobox gene families. This data, in conjunction with recent findings that Six1 is capable of promoting breast cancer initiation and progression, suggest that Six1 may serve as a reasonable chemotherapeutic target in a clinical setting, particularly for those women diagnosed with breast cancer in their childbearing years.

Project description:Since the advent of screening mammography, approximately one-quarter of newly diagnosed breast cancers are at the earliest preinvasive stage of ductal carcinoma in situ (DCIS). Concomitant with this improvement in early detection has been a growing clinical concern that distinguishing aggressive from indolent DCIS is necessary to optimize patient management. Genetically engineered mouse models offer an appealing experimental framework in which to investigate factors that influence and predict progression of preinvasive neoplasias. Because of the small size of early stage carcinomas in mice, high-resolution imaging techniques are required to effectively observe longitudinal progression. The purpose of the present study was to evaluate the feasibility of MRI for assessment of in situ mammary neoplasias and early invasive mammary cancers that stochastically arise in mammary glands of C3(1) SV40 Tag transgenic mice. Additionally, images of normal mammary glands from wild-type FVB/N mice were acquired and compared with those from transgenic mice. Sixteen mice underwent MR examinations employing axial two-dimensional multi-slice gradient recalled echo scans (TR/TE =∼1000/5.5 ms) with fat suppression in a two-step process targeting both the upper and lower mammary glands. MRI successfully detected in situ and early invasive neoplasias in transgenic mice with high sensitivity and specificity. The average signal-to-noise ratio (SNR) of in situ lesions on fat-suppressed high-resolution T(1) -weighted images was 22.9, which was lower than that of invasive tumors, lymph nodes and muscle (average SNR of 29.5-34.9, p < 0.0001) but significantly higher than that of normal mammary tissue (average SNR = 5.5, p < 0.0001). Evaluation of wild-type mammary glands revealed no cancerous or benign lesions, and comparable image contrast characteristics (average SNR = 5.2) as compared with normal tissue areas of transgenic mice. This present study demonstrates that MRI is an excellent candidate for performing longitudinal assessment of early stage mammary cancer disease progression and response to therapy in the transgenic model system.

Dataset Information

Identification and characterization of new miRNAs cloned from normal mouse mammary gland.

Publications

Identification and characterization of new miRNAs cloned from normal mouse mammary gland.

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