Control of breast cancer growth and initiation by the stem cell-associated transcription factor TCF3.

Regulatory factors controlling stem cell identity and self-renewal are often active in aggressive cancers and are thought to promote their growth and progression. TCF3 (also known as TCF7L1) is a member of the TCF/LEF transcription factor family that is central in regulating epidermal and embryonic stem cell identity. We found that TCF3 is highly expressed in poorly differentiated human breast cancers, preferentially of the basal-like subtype. This suggested that TCF3 is involved in the regulation of breast cancer cell differentiation state and tumorigenicity. Silencing of TCF3 dramatically decreased the ability of breast cancer cells to initiate tumor formation, and led to decreased tumor growth rates. In culture, TCF3 promotes the sphere formation capacity of breast cancer cells and their self-renewal. We found that in contrast to ES cells, where it represses Wnt-pathway target genes, TCF3 promotes the expression of a subset of Wnt-responsive genes in breast cancer cells while repressing another distinct target subset. In the normal mouse mammary gland, Tcf3 is highly expressed in terminal end buds, structures that lead duct development. Primary mammary cells are dependent on Tcf3 for mammosphere formation, and its overexpression in the developing gland disrupts ductal growth. Our results identify TCF3 as a central regulator of tumor growth and initiation, and a novel link between stem cells and cancer.

• Publication year

  2012

• Venue

  Cancer Research

• Publication date

  2012-07-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1158/0008-5472.CAN-12-0119PMID 23090119
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• In the normal mouse mammary gland, TCF3 is enriched in terminal end buds, primary mammary cells depend on it for mammosphere formation, and its overexpression disrupts ductal growth; in breast cancer cells, it regulates a subset of Wnt-responsive genes.

  Confidence 0.92

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• TCF3 promotes sphere formation capacity and self-renewal in breast cancer cells grown in culture.

  Confidence 0.95

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• Silencing TCF3 reduces breast cancer cell tumor initiation and lowers tumor growth rates.

  Confidence 0.97

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• TCF3 is highly expressed in poorly differentiated breast cancers, with preferential expression in the basal-like subtype.

  Confidence 0.95

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• basal-like subtype

  cancer subtype

  A molecular subtype of breast cancer defined by basal-like gene-expression characteristics.

  Aliases: basal-like

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• ductal growth

  developmental process

  The elongation and branching of mammary ducts during gland development.

  Aliases: mammary ductal growth

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• mammosphere formation

  culture assay

  Growth of mammary-derived cells as floating spheroid structures under nonadherent culture conditions.

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• poorly differentiated breast cancer

  cancer feature

  Breast cancer with limited cellular differentiation of the tumor tissue.

  Aliases: poorly differentiated human breast cancer

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• primary mammary cells

  cell population

  Cells isolated directly from mammary tissue before long-term culture or transformation.

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• self-renewal

  stem cell property

  The capacity of a cell population to maintain itself through successive rounds of growth and division.

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) reviewmexicorea (qjvnbu8xg3) reviewAK (4715169a40) reviewAnonymous (12632b8b5f) review
• sphere formation

  cell phenotype, culture assay

  The ability of cells to grow as spheroid colonies in culture.

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• tcf3

  transcription factor, gene

  A TCF/LEF family transcription factor also known as TCF7L1 that is examined here in breast cancer and mammary gland contexts.

  Aliases: TCF7L1

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• terminal end buds

  anatomical structure

  Bulbous structures at the tips of developing mammary ducts that drive ductal extension.

  Aliases: TEBs

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• tumor growth

  tumor phenotype

  The expansion of an established tumor over time.

  Aliases: tumor growth rate

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• tumor initiation

  tumor phenotype

  The capacity of cells to start a new tumor after introduction into a host.

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• wnt-responsive genes

  gene set

  Genes whose expression is regulated in response to Wnt signaling activity.

  Aliases: Wnt target genes

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• Supplemental Table 1

  2016cited by this paper
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