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ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium.

ABSTRACT: Breast cancer progression involves genetic changes and changes in the extracellular matrix (ECM). To test the importance of the ECM in tumor cell dissemination, we cultured epithelium from primary human breast carcinomas in different ECM gels. We used basement membrane gels to model the normal microenvironment and collagen I to model the stromal ECM. In basement membrane gels, malignant epithelium either was indolent or grew collectively, without protrusions. In collagen I, epithelium from the same tumor invaded with protrusions and disseminated cells. Importantly, collagen I induced a similar initial response of protrusions and dissemination in both normal and malignant mammary epithelium. However, dissemination of normal cells into collagen I was transient and ceased as laminin 111 localized to the basal surface, whereas dissemination of carcinoma cells was sustained throughout culture, and laminin 111 was not detected. Despite the large impact of ECM on migration strategy, transcriptome analysis of our 3D cultures revealed few ECM-dependent changes in RNA expression. However, we observed many differences between normal and malignant epithelium, including reduced expression of cell-adhesion genes in tumors. Therefore, we tested whether deletion of an adhesion gene could induce sustained dissemination of nontransformed cells into collagen I. We found that deletion of P-cadherin was sufficient for sustained dissemination, but exclusively into collagen I. Our data reveal that metastatic tumors preferentially disseminate in specific ECM microenvironments. Furthermore, these data suggest that breaks in the basement membrane could induce invasion and dissemination via the resulting direct contact between cancer cells and collagen I.

SUBMITTER: Nguyen-Ngoc KV

PROVIDER: S-EPMC3465416 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium.

Nguyen-Ngoc Kim-Vy KV Cheung Kevin J KJ Brenot Audrey A Shamir Eliah R ER Gray Ryan S RS Hines William C WC Yaswen Paul P Werb Zena Z Ewald Andrew J AJ

Proceedings of the National Academy of Sciences of the United States of America 20120823 39

Breast cancer progression involves genetic changes and changes in the extracellular matrix (ECM). To test the importance of the ECM in tumor cell dissemination, we cultured epithelium from primary human breast carcinomas in different ECM gels. We used basement membrane gels to model the normal microenvironment and collagen I to model the stromal ECM. In basement membrane gels, malignant epithelium either was indolent or grew collectively, without protrusions. In collagen I, epithelium from the s ...[more]

PMID: 22923691

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Project description:IntroductionThe molecular circuitry of different cell types dictates their normal function as well as their response to oncogene activation. For instance, mice lacking the Wip1 phosphatase (also known as PPM1D; protein phosphatase magnesium-dependent 1D) have a delay in HER2/neu (human epidermal growth factor 2), but not Wnt1-induced mammary tumor formation. This suggests a cell type-specific reliance on Wip1 for tumorigenesis, because alveolar progenitor cells are the likely target for transformation in the MMTV(mouse mammary tumor virus)-neu but not MMTV-wnt1 breast cancer model.MethodsIn this study, we used the Wip1-knockout mouse to identify the cell types that are dependent on Wip1 expression and therefore may be involved in the early stages of HER2/neu-induced tumorigenesis.ResultsWe found that alveolar development during pregnancy was reduced in Wip1-knockout mice; however, this was not attributable to changes in alveolar cells themselves. Unexpectedly, Wip1 allows steroid hormone-receptor-positive cells but not alveolar progenitors to activate STAT5 (signal transducer and activator of transcription 5) in the virgin state. In the absence of Wip1, hormone-receptor-positive cells have significantly reduced transcription of RANKL (receptor activator of nuclear factor kappa-B ligand) and IGF2 (insulin-like growth factor 2), paracrine stimulators of alveolar development. In the MMTV-neu model, HER2/neu activates STAT5 in alveolar progenitor cells independent of Wip1, but HER2/neu does not override the defect in STAT5 activation in Wip1-deficient hormone-sensing cells, and paracrine stimulation remains attenuated. Moreover, ERK (extracellular signal-regulated kinase) activation by HER2/neu in hormone-sensing cells is also Wip1 dependent.ConclusionsWe identified Wip1 as a potentiator of prolactin and HER2/neu signaling strictly in the molecular context of hormone-sensing cells. Furthermore, our findings highlight that hormone-sensing cells convert not only estrogen and progesterone but also prolactin signals into paracrine instructions for mammary gland development. The instructive role of hormone-sensing cells in premalignant development suggests targeting Wip1 or prolactin signaling as an orthogonal strategy for inhibiting breast cancer development or relapse.

Dataset Information

ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium.

Publications

ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium.

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