Novel Cell Culture Technique for Primary Ductal Carcinoma In Situ: Role of Notch and Epidermal Growth Factor Receptor Signaling Pathways

Farnie, Gillian; Clarke, Robert B.; Spence, Katherine; Pinnock, N.; Brennan, Keith; Anderson, Neil G.; Bundred, Nigel

doi:10.1093/jnci/djk133

Cited by 292 publications

(285 citation statements)

References 33 publications

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“…This assay is used as a stem-like functional assay that allows the propagation of mammary epithelial and breast tumour cells in an undifferentiated state based on their ability to proliferate in suspension (Dontu et al, 2003;Ponti et al, 2005;Farnie et al, 2007) and has been used for cancer stem-like specific drug screening in MCF7 cells (Zhou et al, 2007;Ao et al, 2011). We did observe induction of Sox2 expression in mammospheres obtained from human breast tumour cell cultures, and from MCF7 and T47D cells.…”

Section: Sox2 Activation In Breast Cancer Stem Cellsmentioning

confidence: 82%

Sox2 expression in breast tumours and activation in breast cancer stem cells

Leis¹,

Eguiara²,

et al. 2011

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The cancer stem cell (CSC) model does not imply that tumours are generated from transformed tissue stem cells. The target of transformation could be a tissue stem cell, a progenitor cell, or a differentiated cell that acquires selfrenewal ability. The observation that induced pluripotency reprogramming and cancer are related has lead to the speculation that CSCs may arise through a reprogramming-like mechanism. Expression of pluripotency genes (Oct4, Nanog and Sox2) was tested in breast tumours by immunohistochemistry and it was found that Sox2 is expressed in early stage breast tumours. However, expression of Oct4 or Nanog was not found. Mammosphere formation in culture was used to reveal stem cell properties, where expression of Sox2, but not Oct4 or Nanog, was induced. Over-expression of Sox2 increased mammosphere formation, effect dependent on continuous Sox2 expression; furthermore, Sox2 knockdown prevented mammosphere formation and delayed tumour formation in xenograft tumour initiation models. Induction of Sox2 expression was achieved through activation of the distal enhancer of Sox2 promoter upon sphere formation, the same element that controls Sox2 transcription in pluripotent stem cells. These findings suggest that reactivation of Sox2 represents an early step in breast tumour initiation, explaining tumour heterogeneity by placing the tumour-initiating event in any cell along the axis of mammary differentiation.

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Section: Sox2 Activation In Breast Cancer Stem Cellsmentioning

confidence: 82%

Sox2 expression in breast tumours and activation in breast cancer stem cells

Leis¹,

Eguiara²,

et al. 2011

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“…Both DAPT and Compound E are chemical inhibitors of the complex. DAPT reduces ductal carcinoma in situ mammosphere formation (Farnie et al, 2007) and pancreatic cancer cell growth (Kimura et al, 2007). Another g-secretase inhibitor, MRK-003, reduces tumour cell proliferation, inhibits serum independence, and induces apoptosis of lung cancer cell lines in vitro and in vivo using mouse xenograft models (Konishi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer, the g-secretase inhibitor DAPT ]-S-phenylglycine t-butyl ester) has been shown to effectively reduce DCIS-induced mammosphere formation (Farnie et al, 2007). We therefore investigated the effects of commercially available g-secretase inhibitors on the proliferation/survival of normal and malignant breast cancer cell lines, their effects on g-secretase component expression and the possible mechanisms involved.…”

mentioning

confidence: 99%

Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells

et al. 2009

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g-Secretase activity is vital for the transmembrane cleavage of Notch receptors and the subsequent migration of their intracellular domains to the nucleus. Notch overexpression has been associated with breast, colon, cervical and prostate cancers. We tested the effect of three different g-secretase inhibitors (GSIs) in breast cancer cells. One inhibitor (GSI1) was lethal to breast cancer cell lines at concentrations of 2 mM and above but had a minimal effect on the non-malignant breast lines. GSI1 was also cytotoxic for a wide variety of cancer cell lines in the NCI60 cell screen. GSI1 treatment resulted in a marked decrease in g-secretase activity and downregulation of the Notch signalling pathway with no effects on expression of the g-secretase components or ligands. Flow cytometric and western blot analyses indicated that GSI1 induces a G2/M arrest leading to apoptosis, through downregulation of Bcl-2, Bax and Bcl-XL. GSI1 also inhibited proteasome activity. Thus, the g-secretase inhibitor GSI1 has a complex mode of action to inhibit breast cancer cell survival and may represent a novel therapy in breast cancer.

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“…The overall pattern of Notch expression and its downstream genes is indeed complicated. Clearly, other non-IBC and ductal carcinoma in situ cell lines express Notch family members (Farnie et al, 2007). The MDA-MB-231 line expresses Notch 1 and Notch 4.…”

Section: Notch 3 Dependency Of Ibc Embolus Y Xiao Et Almentioning

confidence: 99%

The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction

Xiao

Zou

et al. 2010

Oncogene

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Novel Cell Culture Technique for Primary Ductal Carcinoma In Situ: Role of Notch and Epidermal Growth Factor Receptor Signaling Pathways

Abstract: We describe a novel primary culture technique for DCIS. Inhibition of the EGFR or Notch signaling pathways reduced DCIS MFE.

Cited by 292 publications

References 33 publications

Sox2 expression in breast tumours and activation in breast cancer stem cells

Sox2 expression in breast tumours and activation in breast cancer stem cells

Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells

The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction

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