Biological and Molecular Heterogeneity of Breast Cancers Correlates with Their Cancer Stem Cell Content

Pece, Salvatore; Tosoni, Daniela; Confalonieri, Stefano; Mazzarol, Giovanni; Vecchi, Manuela; Ronzoni, Simona; Bernard, Loris; Viale, Giuseppe; Pelicci, Pier Giuseppe; Fiore, Pier Paolo Di

doi:10.1016/j.cell.2009.12.007

Cited by 836 publications

(810 citation statements)

References 57 publications

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“…In any case, the cross-talk between b-catenin and DNp63 may be of major relevance in the maintenance of normal and cancer epithelial stem cells, a process in which both factors have important roles. In a physiological context, b-catenin and DNp63 regulate proliferation or differentiation of epidermal and mammary progenitor/stem cells (Senoo et al, 2007;Ambler and Maatta, 2009;Pece et al, 2010). In tumours, they have been implicated in the maintenance of the stemness of cancer stem cells (Katoh and Katoh, 2007;Zucchi et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

et al. 2011

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The DNp63 protein, a product of the TP63 gene that lacks the N-terminal domain, has a critical role in the maintenance of self renewal and progenitor capacity in several types of epithelial tissues. DNp63 is frequently overexpressed in squamous cell carcinoma (SCC) and in some other epithelial tumours. This overexpression may contribute to tumour progression through dominantnegative effects on the transcriptionally active (TA) isoforms of the p53 family (TAp63, TAp73 and p53), as well as through independent mechanisms. However, the molecular basis of DNp63 overexpression is not fully understood. Here, we show that the expression of DNp63 is regulated by the Wnt/b-catenin pathway in human hepatocellular carcinoma (HCC) and SCC cell lines. This regulation operates in particular through TCF/LEF sites present in the P2 promoter of TP63. In addition, we show that DNp63 and b-catenin are frequently coexpressed and accumulated in oesophageal SCC, but not in HCC. These results suggest that activation of the b-catenin pathway may contribute to overexpression of DNp63 during tumour progression, in a cell type-specific manner.

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Section: Discussionmentioning

confidence: 99%

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

et al. 2011

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“…p53 in mammary stem cells Adult mammary SCs can be cultured in vitro in nonadherent conditions as floating aggregates called mammospheres [31,32]. We have recently characterized both human [33] and mouse [34] mammospheres from normal tissues (wild type, WT) as spherical colonies derived from the clonal expansion of individual mammary SCs. Mammospheres contain an average of 1 SC per sphere and can be propagated over several passages of dissociation and reformation.…”

Section: Opinionmentioning

confidence: 99%

The emerging role of p53 in stem cells

Bonizzi

Cicalese

Insinga

et al. 2012

Trends in Molecular Medicine

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“…The ability to form colonies in liquid or on extracellular matrix (Matrigel) is a hallmark of normal mammary stem and progenitor cell populations, and of stem-like breast cancer cells (7,24,25).…”

Section: Ezh2 Promotes the Colony Formation Capacity Of Basal-like Brmentioning

confidence: 99%

EZH2 promotes a bi-lineage identity in basal-like breast cancer cells

et al. 2012

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The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitorassociated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a "bi-lineage" differentiation state, in which cells co-express basal-and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal-progenitor gene expression. GATA3 levels increase upon EZH2 silencing, mediating a decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition.

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Biological and Molecular Heterogeneity of Breast Cancers Correlates with Their Cancer Stem Cell Content

Cited by 836 publications

References 57 publications

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

The emerging role of p53 in stem cells

EZH2 promotes a bi-lineage identity in basal-like breast cancer cells

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