Wnt pathway and breast cancer

Mohinta, Sonia

doi:10.2741/2368

Cited by 54 publications

(43 citation statements)

References 145 publications

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“…Interestingly, of those genes with evidence for clinical relevance, Wnt pathway alterations (eg, WNT5A, VANGL1, WISP1) are particularly predominant in the comparison between 21PTci and 21NTci (representing the ADH to DCIS transition). This is consistent with recent studies implicating both the canonical and noncanonical Wnt-signaling pathways in initiation and maintenance of breast tumorigenesis (reviewed in Mohinta et al 61 ) as well as in cancer stem cell self renewal and the initiation of the epithelial to mesenchymal transition. 62 In particular, the planar cell polarity (PCP) pathway (a non-canonical Wnt pathway), involving ligand WNT5A, has been said to have either inhibitory or promoting roles in various cancers, depending on the context (reviewed in Kikuchi and Yamamoto 63 ).…”

Section: Discussionsupporting

confidence: 93%

Human 21T breast epithelial cell lines mimic breast cancer progression in vivo and in vitro and show stage-specific gene expression patterns

Souter

Andrews

Cook

et al. 2010

Laboratory Investigation

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Early breast cancer progression involves advancement through specific morphological stages including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive mammary carcinoma (IMC), although not necessarily always in a linear fashion. Observational studies have examined genetic, epigenetic and gene expression differences in breast tissues representing these stages of progression, but model systems which would allow for experimental testing of specific factors influencing transition through these stages are scarce. The 21T series cell lines, all originally derived from the same patient with metastatic breast cancer, have been proposed to represent a mammary tumor progression series. We report here that three of the 21T cell lines indeed mimic specific stages of human breast cancer progression (21PT-derived cells, ADH; 21NT-derived cells, DCIS; 21MT-1 cells, IMC) when grown in the mammary fat pad of nude mice, albeit after a year. To develop a more rapid, readily manipulatable in vitro assay for examining the biological differences between these cell lines, we have used a 3D Matrigel system. When the three cell lines were grown in 3D Matrigel, they showed characteristic morphologies, in which quantifiable aspects of stage-specific in vivo behaviors (ie, differences in acinar structure formation, cell polarization, colony morphology, cell proliferation, cell invasion) were recapitulated in a reproducible fashion. Gene expression profiling revealed a characteristic pattern for each of the three cell lines. Interestingly, Wnt pathway alterations are particularly predominant in the early transition from 21PTci (ADH) to 21NTci (DCIS), whereas alterations in expression of genes associated with control of cell motility and invasion phenomena are more prominent in the later transition of 21NTci (DCIS) to 21MT-1 (IMC). This system thus reveals potential therapeutic targets and will provide a means of testing the influences of identified genes on transitions between these stages of pre-malignant to malignant growth. KEYWORDS: breast cancer; tumor progression; expression microarray; atypical ductal hyperplasia; ductal carcinoma in situ; invasive mammary carcinoma Pathological and epidemiological evidence has led to a histological model of breast cancer evolution, in which stem cells from the terminal duct lobular unit give rise to atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia, which can then progress to ductal carcinoma in situ (DCIS) or lobular carcinoma in situ, respectively, and eventually to invasive mammary carcinomas (IMC).1-6 These histological patterns are, however, most likely only rough phenotypic indications of underlying cellular and molecular events determining progression, 7 and may not necessarily occur in a linear fashion. There is currently much interest in identifying the nature of the cellular and molecular events involved, not only for use in determining at which point a lesion is most likely to progress to malignancy, but also in hopes of finding a way to halt ...

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Section: Discussionsupporting

confidence: 93%

Human 21T breast epithelial cell lines mimic breast cancer progression in vivo and in vitro and show stage-specific gene expression patterns

Souter

Andrews

Cook

et al. 2010

Laboratory Investigation

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“…Wnt signaling has been implicated in several human tumors, among which are skin, connective tissue, colon, gastric, lung, breast, and prostate (3)(4)(5)(6)(7)(8)(9). In addition, recent studies highlighted the potential role for Wnt signaling in STS.…”

Section: Introductionmentioning

confidence: 99%

Frzb, a Secreted Wnt Antagonist, Decreases Growth and Invasiveness of Fibrosarcoma Cells Associated with Inhibition of Met Signaling

Guo¹,

Xie²,

Rubin³

et al. 2008

Cancer Research

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Soft tissue sarcomas (STS) have a strong propensity for aggressive growth and metastasis. We showed that the secreted Wnt antagonist Frzb exhibited potent antitumor activity against prostate cancer, an epithelial type of malignancy. In this study, we further showed the antitumor efficacy of Frzb in STS, a mesenchymal group of cancer. Frzb transfection of HT1080 ( fibrosarcoma) and SW872 (liposarcoma) cell lines and their conditioned media resulted in a significant reduction in cellular invasion, motility, and colony formation in soft agar compared with vector controltransfected cells. In a xenograft mouse model, Frzb dramatically suppressed tumor growth of HT1080 cells in nude mice. In a tail-vein injection metastatic model, Frzb-transfected HT1080 cells formed fewer and smaller lung nodules than vector control cells. In addition, we identified new mechanisms for Frzb antitumor activities. Frzb reduced c-Met expression and inhibited Met-mediated signaling, associated with up-regulation of epithelial markers (i.e., keratins 8 and 18) and down-regulation of mesenchymal markers (i.e., vimentin, N-cadherin, fibronectin, Slug, and Twist). Similar to Frzb, silencing of c-Met by short hairpin RNA or using a dominant-negative LRP5 receptor also suppressed Met signaling, leading to reduced cellular motility, invasion, and in vivo tumor growth. Given recent studies indicating an important role of c-Met in sarcoma development and progression, our data showed that Frzb expression was significantly inversely correlated with Met expression in both STS cell lines and tissues. These results suggested the usefulness of Frzb in modulating Met signaling as a new treatment strategy for STS. [Cancer Res 2008;68(9):3350-60]

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“…1 Despite advances in genetic and biochemical analyses, which have deciphered many specific molecular signatures, a deeper molecular basis of transformation is still unknown in this tumor. [2][3][4][5] Recently, an increasing body of evidence has shown that deregulation of miRNAs is associated with cancer development.…”

Section: Introductionmentioning

confidence: 99%