These data identify EGFR as a major target for ΔNp63 regulation that influences cancer cell adhesion in basal-like triple-negative breast cancer.

Triple-negative breast cancers (TNBC) comprise a heterogeneous subgroup of tumors with a generally poor prognosis. Subclassification of TNBC based on genomic analyses shows that basal-like TNBCs, specifically the basal A or BL2 subtype, are characterized by the expression of ΔNp63, a transcription factor that has been attributed a variety of roles in the regulation of proliferation, differentiation, and cell survival. To investigate the role(s) of p63 in basal-like breast cancers, we used HCC1806 cells that are classified as basal A/BL2. We show that these cells endogenously express p63, mainly as the ΔNp63α isoform. TP63 gene knockout by CRISPR resulted in viable cells that proliferate more slowly and adhere less tightly, with an increased rate of migration. Analysis of adhesion-related gene expression revealed a complex set of alterations in p63-depleted cells, with both increased and decreased adhesion molecules and adhesion substrates compared to parental cells expressing p63. Examination of the phenotype of these cells indicated that endogenous p63 is required to suppress the expression of luminal markers and maintain the basal epithelial phenotype, with increased levels of both CK8 and CK18 and a reduction in N-cadherin levels in cells lacking p63. On the other hand, the level of CK5 was not decreased and ER was not increased, indicating that p63 loss is insufficient to induce full luminal-type differentiation. Taken together, these data demonstrate that p63 exerts multiple pro-oncogenic effects on cell differentiation, proliferation and adhesion in basal-like breast cancers.

Backgroundp63, a member of the p53 protein family, plays key roles in epithelial development and carcinogenesis. In breast cancer, p63 expression has been found predominantly in basal-A (epithelial-type) triple-negative breast carcinomas (TNBC). To investigate the functional role of p63 in basal-A TNBC, we created MDA-MB-468 cell lines with inducible expression of the two major N-terminal p63 isoforms, TAp63α and ∆Np63α.ResultsTAp63α did not have significant effect on gene expression profile and cell phenotype, whilst the main effect of ΔNp63α was reduction of cell adhesion. Gene expression profiling revealed genes involved in cell adhesion and migration whose expression relies on overexpression of ΔNp63α. Reduced cell adhesion also led to decreased cell proliferation in vitro and in vivo. Similar data were obtained in another basal-A cell line, BT-20, but not in BT-549 basal-B (mesenchymal-like) TNBC cells.ConclusionsIn basal-A TNBC cells, ∆Np63α has much stronger effects on gene expression than TAp63α. Although p63 is mentioned mostly in connection with breast cell differentiation and stem cell regulation, we showed that a major effect of p63 is regulation of cell adhesion, a process important in metastasis and invasion of tumour cells. That this effect is not seen in mesenchymal-type TNBC cells suggests lineage-dependent functions, mirroring the expression of ∆Np63α in primary human breast cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2808-x) contains supplementary material, which is available to authorized users.

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Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno Souhrn Ačkoliv úspěšnost léčby nádorových onemocnění se každoročně zvyšuje, rezistence k léčivům je nadále hlavní příčina úmrtí pacientů s rakovinou. Počáteční léčba často zanechává "zbytkové" (reziduální) onemocnění, které vede k opětovnému rozvoji nádoru, případně ke ztrátě jeho citlivosti k použité léčbě. Vznik reziduálního onemocnění je ovlivněn přítomností nádorových kmenových buněk (CSCs). Jedná se o malou populaci buněk schopných sebeobnovy a diferenciace. Předpokládá se, že tyto buňky jsou odpovědné za vznik, růst, metastazovaní a udržení nádoru a také za jeho lékovou rezistenci. V poslední době je velká pozornost věnována vývoji terapií zaměřených na eliminaci CSCs a na identifi kaci klíčových molekul zapojených do kontroly vlastností charakteristických pro populaci CSCs. Tento článek shrnuje základní poznatky o mechanizmech lékové rezistence ve vztahu k populaci nádorových kmenových buněk. Klíčová slova léková rezistence − nádorové kmenové buňky − membránové transportní proteiny-přeměna epitelové buňky na mezenchymovou-mikroprostředí nádoru − apoptóza Summary Although the success of anticancer treatments has been increasing annually, drug resistance remains the dominant cause of death of cancer patients. Initial therapy often leaves residual dis ease that leads to repeated tumor development or to loss of its sensitivity to available therapy. One reason of residual disease formation is the presence of cancer stem cells (CSCs). CSCs have been identifi ed as a small population of cells that is capable of self-renewal and diff erentiation. It is supposed that these cells are responsible for cancer initiation, progression, metastasis, recurrence and drug resistance. Over the past years, much attention has been paid to development of CSCs-related therapies and to identifi cation of key molecules involved in controlling the specifi c properties of CSCs populations. This article reviews the basic mechanisms of drug resistance in relation to cancer stem cells.

In the original published online paper, the name of the fifth author was incorrectly captured. The author name should have been Borivoj Vojtesek not Borivoj Votesek. The corrected author name is shown above.