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Identification of a mammary transforming gene (MAT1) associated with mouse mammary carcinogenesis.

ABSTRACT: We have developed an efficient in vitro transformation system using N-methyl-N-nitrosourea that allows us to study the role of hormones and growth factors in mouse mammary tumorigenesis. Utilizing this system, we reported earlier that mammary tumors induced in vitro with N-methyl-N-nitrosourea in the presence of mammogenic hormones (progesterone and prolactin) contain predominately an activated c-Ki-ras protooncogene with a G35 --> A35 transitional mutation in the 12th codon. Mammary tumors induced in the presence of another mitogen, lithium (Li), do not have a mutation in the c-Ki-ras protooncogene. By using an expression cloning system, a plasmid clone containing a 1.75-kb cDNA insert has been isolated from this group of tumors. Nucleic acid sequence analysis of the insert reveals that it has a short open reading frame of 61 amino acids and that it does not have sequence homology with any known gene. The gene, designated MAT1, can neoplastically transform NIH 3T3 cells and also the mammary epithelial cell line TM3. Expression of this gene occurs in normal mouse tissues including mammary gland and is overexpressed in the original mammary tumors as indicated by Northern blot analysis. In vitro transcription and translation of the clone shows a protein product of 6000 Da, which agrees with the predicted open reading frame.

SUBMITTER: Bera TK

PROVIDER: S-EPMC44902 | biostudies-other | 1994 Oct

REPOSITORIES: biostudies-other

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Identification of a mammary transforming gene (MAT1) associated with mouse mammary carcinogenesis.

Bera T K TK Guzman R C RC Miyamoto S S Panda D K DK Sasaki M M Hanyu K K Enami J J Nandi S S

Proceedings of the National Academy of Sciences of the United States of America 19941001 21

We have developed an efficient in vitro transformation system using N-methyl-N-nitrosourea that allows us to study the role of hormones and growth factors in mouse mammary tumorigenesis. Utilizing this system, we reported earlier that mammary tumors induced in vitro with N-methyl-N-nitrosourea in the presence of mammogenic hormones (progesterone and prolactin) contain predominately an activated c-Ki-ras protooncogene with a G35 --> A35 transitional mutation in the 12th codon. Mammary tumors indu ...[more]

PMID: 7937892

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Project description:Transforming growth factor beta (TGF?) plays a major role in the regulation of tumor initiation, progression, and metastasis. It is depended on the type II TGF? receptor (T?RII) for signaling. Previously, we have shown that deletion of T?RII in mammary epithelial of MMTV-PyMT mice results in shortened tumor latency and increased lung metastases. However, active TGF? signaling increased the number of circulating tumor cells and metastases in MMTV-Neu mice. In the current study, we describe a newly discovered connection between attenuated TGF? signaling and human epidermal growth factor receptor 2 (HER2) signaling in mammary tumor progression.All studies were performed on MMTV-Neu mice with and without dominant-negative T?RII (DNIIR) in mammary epithelium. Mammary tumors were analyzed by flow cytometry, immunohistochemistry, and immunofluorescence staining. The levels of secreted proteins were measured by enzyme-linked immunosorbent assay. Whole-lung mount staining was used to quantitate lung metastasis. The Cancer Genome Atlas (TCGA) datasets were used to determine the relevance of our findings to human breast cancer.Attenuated TGF? signaling led to a delay tumor onset, but increased the number of metastases in MMTVNeu/DNIIR mice. The DNIIR tumors were characterized by increased vasculogenesis, vessel leakage, and increased expression of vascular endothelial growth factor (VEGF). During DNIIR tumor progression, both the levels of CXCL1/5 and the number of CD11b+Gr1+ cells and T cells decreased. Analysis of TCGA datasets demonstrated a significant negative correlation between TGFBR2 and VEGF genes expression. Higher VEGFA expression correlated with shorter distant metastasis-free survival only in HER2+ patients with no differences in HER2-, estrogen receptor +/- or progesterone receptor +/- breast cancer patients.Our studies provide insights into a novel mechanism by which epithelial TGF? signaling modulates the tumor microenvironment, and by which it is involved in lung metastasis in HER2+ breast cancer patients. The effects of pharmacological targeting of the TGF? pathway in vivo during tumor progression remain controversial. The targeting of TGF? signaling should be a viable option, but because VEGF has a protumorigenic effect on HER2+ tumors, the targeting of this protein could be considered when it is associated with attenuated TGF? signaling.

Dataset Information

Identification of a mammary transforming gene (MAT1) associated with mouse mammary carcinogenesis.

Publications

Identification of a mammary transforming gene (MAT1) associated with mouse mammary carcinogenesis.

Similar Datasets

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