Prognostic Significance of TGF-α Expression in Breast Cancer

Auvinen, Päivi; Lipponen, P; Kataja, Vesa; Johansson, Risto; Syrjänen, Karí

doi:10.3109/02841869609100717

Cited by 16 publications

(11 citation statements)

References 20 publications

(13 reference statements)

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“…Transforming growth factor a (TGFa) is a strong mitogen for a variety of cell types (Lee et al, 1995;Dickson et al, 1995) and is overexpressed in over 50% of breast cancer cases (Auvinen et al, 1996;Pilichowska et al, 1997;Panico et al, 1996). Virgin female mice carrying a tgfa transgene under control of the MMTV or metallothionein-1 (MT) promoters develop mammary epithelial hyperplasia, but not mammary cancer, unless the mice undergo multiple pregnancies (Sandgren et al, 1990;Jhappan et al, 1990;Matsui et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Cell cycle basis for the onset and progression of c-Myc-induced, TGFα-enhanced mouse mammary gland carcinogenesis

et al. 2000

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Using single and double transgenic mouse models, we investigated how c-Myc modulates the mammary epithelial cell cycle to induce cancer and how TGFa enhanced the process. In c-myc transgenic mice, c-myc expression was high in the hyperplastic mammary epithelium and in the majority of tumor areas. However, the tumors displayed focal areas of low expression of cmyc but high rates of proliferation. In contrast to E2F1 and cyclin A2, which were induced and co-localized with c-myc expression, induction of cyclins D1 and E occurred only in these tumor foci. Overexpression of cyclin D1 also occurred in the hyperplastic epithelium of tgfa-single and tgfa/c-myc-double transgenic mice. In tgfa/c-myc tumors, cells positive for cyclins D1 and E were randomly spread, without showing a reciprocal relationship to c-myc expression. In contrast to c-myc tumors, most tgfa/c-myc tumors showed undetectable levels of retinoblastoma protein (pRB), and the loss of pRB occurred in some cases at the mRNA level. These results suggest that E2F1 and cyclin A2 may be induced by c-Myc to mediate the onset of mammary cancer, whereas overexpression of cyclins D1 and E may occur later to facilitate tumor progression. TGFa may play its synergistic role, at least in part, by inducing cyclin D1 and facilitating the loss of pRB.

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Section: Introductionmentioning

confidence: 99%

Cell cycle basis for the onset and progression of c-Myc-induced, TGFα-enhanced mouse mammary gland carcinogenesis

et al. 2000

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“…TGF-alpha is a known target of HIF1-alpha [ 20 ] but it was not activated within our HIF1-alpha induced or hypoxic cultured cells. TGF-alpha has been previously suggested as a marker of poor outcome at follow-up and specifically for lymph node metastasis [ 21 ], whether this is linked to hypoxia is yet to be seen but this kind of change in the bulk of the tumour may explain how HIF1-alpha induction by hypoxia in the primary tumour can increase metastasis even though this recurrence often happens many years after removal of the primary tumour.…”

Section: Discussionmentioning

confidence: 99%

HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells

et al. 2018

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BackgroundHypoxia stimulates metastasis in cancer and is linked to poor patient prognosis. In tumours, oxygen levels vary and hypoxic regions exist within a generally well-oxygenated tumour. However, whilst the heterogeneous environment is known to contribute to metastatic progression, little is known about the mechanism by which heterogeneic hypoxia contributes to cancer progression. This is largely because existing experimental models do not recapitulate the heterogeneous nature of hypoxia.The primary effector of the hypoxic response is the transcription factor Hypoxia inducible factor 1-alpha (HIF1-alpha). HIF1-alpha is stabilised in response to low oxygen levels in the cellular environment and its expression is seen in hypoxic regions throughout the tumour.MethodsWe have developed a model system in which HIF1-alpha can be induced within a sub-population of cancer cells, thus enabling us to mimic the effects of heterogeneic HIF1-alpha expression.ResultsWe show that induction of HIF1-alpha not only recapitulates elements of the hypoxic response in the induced cells but also results in significant changes in proliferation, gene expression and mammosphere formation within the HIF1-alpha negative population.ConclusionsThese findings suggest that the HIF1-alpha expressing cells found within hypoxic regions are likely to contribute to the subsequent progression of a tumour by modifying the behaviour of cells in the non-hypoxic regions of the local micro-environment.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4577-1) contains supplementary material, which is available to authorized users.

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“…TGF-alpha is a known target of HIF1-alpha (18) but it was not activated within our HIF1-alpha induced or hypoxic cultured cells. TGF-alpha has been previously suggested as a marker of poor outcome at follow-up and specifically for lymph node metastasis (19), whether this is linked to hypoxia is yet to be seen but this kind of change in the bulk of the tumour may explain how HIF1-alpha induction by hypoxia in the primary tumour can increase metastasis even though this recurrence often happens many years after removal of the primary tumour.…”

Section: Discussionmentioning

confidence: 99%

HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells

Harrison

Pegg

Thompson

et al. 2018

Preprint

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Hypoxia stimulates metastasis in cancer and is linked to poor patient prognosis. In tumours, oxygen levels vary and hypoxic regions exist within a generally well-oxygenated tumour. However, whilst the heterogeneous environment is known to contribute to metastatic progression, little is known about the mechanism by which heterogeneic hypoxia contributes to cancer progression. This is largely because existing experimental models do not recapitulate the heterogeneous nature of hypoxia. The primary effector of the hypoxic response is the transcription factor Hypoxia inducible factor 1-alpha (HIF1-alpha). HIF1-alpha is stabilised in response to low oxygen levels in the cellular environment and its expression is seen in hypoxic regions throughout the tumour.We have developed a model system in which HIF1-alpha can be induced within a sub-population of cancer cells, thus enabling us to mimic the effects of heterogeneic HIF1-alpha expression.We show that induction of HIF1-alpha not only recapitulates elements of the hypoxic response in the induced cells but also results in significant changes in proliferation, gene expression and mammosphere formation within the HIF1-alpha negative population.These findings suggest that the HIF1-alpha expressing cells found within hypoxic regions are likely to contribute to the subsequent progression of a tumour by modifying the behaviour of cells in the non-hypoxic regions of the local micro-environment.

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Prognostic Significance of TGF-α Expression in Breast Cancer

Cited by 16 publications

References 20 publications

Cell cycle basis for the onset and progression of c-Myc-induced, TGFα-enhanced mouse mammary gland carcinogenesis

Cell cycle basis for the onset and progression of c-Myc-induced, TGFα-enhanced mouse mammary gland carcinogenesis

HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells

HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells

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