Dataset Information

?Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER⁺ and HER2⁺ breast cancers.

ABSTRACT: ?Np63, also known as p40, regulates stemness of normal mammary gland epithelium and provides stem cell characteristics in basal and HER2-driven murine breast cancer models. Whilst ?Np63/p40 is a characteristic feature of normal basal cells and basal-type triple-negative breast cancer, some receptor-positive breast cancers express ?Np63/p40 and its overexpression imparts cancer stem cell-like properties in ER⁺ cell lines. However, the incidence of ER⁺ and HER2⁺ tumours that express ?Np63/p40 is unclear and the phenotype of ?Np63/p40⁺ cells in these tumours remains uncertain. Using immunohistochemistry with p63 isoform-specific antibodies, we identified a ?Np63/p40⁺ tumour cell subpopulation in 100 of 173 (58%) non-triple negative breast cancers and the presence of this population associated with improved survival in patients with ER^- /HER2⁺ tumours (p = 0.006). Furthermore, 41% of ER⁺ /PR⁺ and/or HER2⁺ locally metastatic breast cancers expressed ?Np63/p40, and these cells commonly accounted for <1% of the metastatic tumour cell population that localised to the tumour/stroma interface, exhibited an undifferentiated phenotype and were CD44⁺ /ALDH^- . In vitro studies revealed that MCF7 and T47D (ER⁺ ) and BT-474 (HER2⁺ ) breast cancer cell lines similarly contained a small subpopulation of ?Np63/p40⁺ cells that increased in mammospheres. In vivo, MCF7 xenografts contained ?Np63/p40⁺ cells with a similar phenotype to primary ER⁺ cancers. Consistent with tumour samples, these cells also showed a distinct location at the tumour/stroma interface, suggesting a role for paracrine factors in the induction or maintenance of ?Np63/p40. Thus, ?Np63/p40 is commonly present in a small population of tumour cells with a distinct phenotype and location in ER⁺ and/or HER2⁺ human breast cancers.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6966710 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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∆Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER+ and HER2+ breast cancers.

Liu Yajing Y Nekulova Marta M Nenutil Rudolf R Horakova Iva I Appleyard M Virginia MV Murray Karen K Holcakova Jitka J Galoczova Michaela M Quinlan Philip P Jordan Lee B LB Purdie Colin A CA Vojtesek Borivoj B Thompson Alastair M AM Coates Philip J PJ

The journal of pathology. Clinical research 20191206 1

ΔNp63, also known as p40, regulates stemness of normal mammary gland epithelium and provides stem cell characteristics in basal and HER2-driven murine breast cancer models. Whilst ΔNp63/p40 is a characteristic feature of normal basal cells and basal-type triple-negative breast cancer, some receptor-positive breast cancers express ΔNp63/p40 and its overexpression imparts cancer stem cell-like properties in ER+ cell lines. However, the incidence of ER+ and HER2+ tu ...[more]

PMID: 31591823

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Project description:Breast cancer is a heterogeneous disease comprised of at least five major subtypes. Luminal subtype tumors confer a more favourable patient prognosis, which is in part, attributed to the Estrogen Receptor-alpha (ER) positivity and anti-hormone responsiveness of these tumors. Expression of the forkhead box transcription factor, FOXA1, also correlates with the luminal subtype and patient survival, but is present in a subset of ER-negative tumors. Similarly, FOXA1 is consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, basal breast cancer cell lines do not express FOXA1, and loss of FOXA1 in luminal cells increases migration and invasion, characteristics of the basal subtype. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favourable prognosis, we performed cDNA microarray analyses on luminal FOXA1-positive, ER-positive (MCF7, T47D) and FOXA1-positive, ER-negative (MDA-MB-453, SKBR3) cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal-signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Use of Gene Set Enrichment Analyses (GSEA) as a phenotyping tool revealed that FOXA1 silencing resulted in a transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to both luminal and basal genes within luminal breast cancer cells, suggesting that it not only transactivates luminal genes, but also represses basal-associated genes. From these results we conclude that FOXA1 controls plasticity between basal and luminal cells, playing a dominant role in repressing the basal phenotype, and thus tumor aggressiveness, in luminal breast cancer cells. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward a more aggressive cancer. FOXA1 siRNA treated breast cell lines compared directly to nonspecific siRNA treated cell lines using Agilent 4X44 microarrays.

Dataset Information

?Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER⁺ and HER2⁺ breast cancers.

Publications

∆Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER<sup>+</sup> and HER2<sup>+</sup> breast cancers.

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Dataset Information

?Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER+ and HER2+ breast cancers.

Publications

∆Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER<sup>+</sup> and HER2<sup>+</sup> breast cancers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

?Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER⁺ and HER2⁺ breast cancers.