Uncoupling of PI3K from ErbB3 Impairs Mammary Gland Development but Does Not Impact on ErbB2-Induced Mammary Tumorigenesis

Lahlou, Hicham; Müller, Thomas; Sanguin-Gendreau, Virginie; Birchmeier, Carmen; Muller, William J.

doi:10.1158/0008-5472.can-11-3513

Cited by 21 publications

(28 citation statements)

References 45 publications

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“…Moreover, increased Ras activation could also contribute to PI3K signaling. In a similar study, Erbb3-mediated PI3K signaling was shown to be dispensable for Erbb2-induced mammary tumorigenesis (31). …”

Section: Discussionmentioning

confidence: 92%

ERBB3-Independent Activation of the PI3K Pathway in EGFR-Mutant Lung Adenocarcinomas

et al. 2015

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ERBB3, a member of the Epidermal Growth Factor Receptor (EGFR) family of receptor tyrosine kinases, has been implicated in activation of the phosphatidyl-inositol 3-kinase (PI3K) pathway in human lung adenocarcinomas driven by EGFR mutations. We investigated the contribution of ERBB3 to the initiation, progression and therapeutic response of EGFR-induced lung adenocarcinomas using tetracycline- and tamoxifen- inducible transgenic mouse models. Deletion of Erbb3 at the time of induction of mutant EGFR had no effect on tumorigenesis, demonstrating that ERBB3 is not required to initiate tumorigenesis. Tumors that developed in the absence of ERBB3 remained sensitive to EGFR TKIs and retained activation of the PI3K/AKT pathway. Interestingly, acute loss of Erbb3 suppressed further growth of established EGFRL858R-mediated lung tumors. Four weeks after deletion of Erbb3, the tumors exhibited phosphorylation of EGFR, of the adaptor proteins GAB1 and GAB2 and, of the downstream signaling molecules AKT and ERK suggesting that alternative signaling pathways could compensate for loss of Erbb3. Similar to our observations with mouse tumors, we found that GAB adaptor proteins play a role in ERBB3 independent activation of the PI3K pathway by mutant EGFR in EGFR mutant human cell lines. Finally, in such cell lines, increased levels of phosphorylation of ERBB2 or MET were associated with reduced sensitivity to acute loss of ERBB3, suggesting remarkable plasticity in the signaling pathways regulated by mutant EGFR with important therapeutic implications.

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Section: Discussionmentioning

confidence: 92%

ERBB3-Independent Activation of the PI3K Pathway in EGFR-Mutant Lung Adenocarcinomas

et al. 2015

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“…In the mouse, ErbB3 is required, via phosphoinositide 3-kinase signalling, for the development of the ducts during mammary gland development, but is not essential for the formation of lobules during pregnancy [51,52]. Balko and colleagues reported that ERBB3 expression in the mammary epithelium is highest in the luminal cell populations and lowest in the basal cells, and that loss of ErbB3 in the luminal cell compartment in mice results in an increase in apoptosis of these cells and an expansion of the basal cell population via paracrine signalling [53].…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and functional characterisation of the luminal cell hierarchy of the mammary gland

et al. 2012

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IntroductionThe organisation of the mammary epithelial hierarchy is poorly understood. Our hypothesis is that the luminal cell compartment is more complex than initially described, and that an understanding of the developmental relationships within this lineage will help in understanding the cellular context in which breast tumours occur.MethodsWe used fluorescence-activated cell sorting along with in vitro and in vivo functional assays to examine the growth and differentiation properties of distinct subsets of human and mouse mammary epithelial cells. We also examined how loss of steroid hormones influenced these populations in vivo. Gene expression profiles were also obtained for all the purified cell populations and correlated to those obtained from breast tumours.ResultsThe luminal cell compartment of the mouse mammary gland can be resolved into nonclonogenic oestrogen receptor-positive (ER+) luminal cells, ER+ luminal progenitors and oestrogen receptor-negative (ER-) luminal progenitors. The ER+ luminal progenitors are unique in regard to cell survival, as they are relatively insensitive to loss of oestrogen and progesterone when compared with the other types of mammary epithelial cells. Analysis of normal human breast tissue reveals a similar hierarchical organisation composed of nonclonogenic luminal cells, and relatively differentiated (EpCAM+CD49f+ALDH-) and undifferentiated (EpCAM+CD49f+ALDH+) luminal progenitors. In addition, approximately one-quarter of human breast samples examined contained an additional population that had a distinct luminal progenitor phenotype, characterised by low expression of ERBB3 and low proliferative potential. Parent-progeny relationship experiments demonstrated that all luminal progenitor populations in both species are highly plastic and, at low frequencies, can generate progeny representing all mammary cell types. The ER- luminal progenitors in the mouse and the ALDH+ luminal progenitors in the human appear to be analogous populations since they both have gene signatures that are associated with alveolar differentiation and resemble those obtained from basal-like breast tumours.ConclusionThe luminal cell compartment in the mammary epithelium is more heterogeneous than initially perceived since progenitors of varying levels of luminal cell differentiation and proliferative capacities can be identified. An understanding of these cells will be essential for understanding the origins and the cellular context of human breast tumours.

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“…This gene is included in the group of genes that regulate breast cancer metastasis, as a metastasis suppressor [52]. Whereas no studies have reported an association of this gene with dairy related traits, there is a functional relationship between CD82 and ERBB3 (Receptor tyrosine-protein kinase erbB-3) [53], which is related to normal mammary development [54].…”

Section: Discussionmentioning

confidence: 99%

Application of Selection Mapping to Identify Genomic Regions Associated with Dairy Production in Sheep

et al. 2014

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In Europe, especially in Mediterranean areas, the sheep has been traditionally exploited as a dual purpose species, with income from both meat and milk. Modernization of husbandry methods and the establishment of breeding schemes focused on milk production have led to the development of “dairy breeds.” This study investigated selective sweeps specifically related to dairy production in sheep by searching for regions commonly identified in different European dairy breeds. With this aim, genotypes from 44,545 SNP markers covering the sheep autosomes were analysed in both European dairy and non-dairy sheep breeds using two approaches: (i) identification of genomic regions showing extreme genetic differentiation between each dairy breed and a closely related non-dairy breed, and (ii) identification of regions with reduced variation (heterozygosity) in the dairy breeds using two methods. Regions detected in at least two breeds (breed pairs) by the two approaches (genetic differentiation and at least one of the heterozygosity-based analyses) were labeled as core candidate convergence regions and further investigated for candidate genes. Following this approach six regions were detected. For some of them, strong candidate genes have been proposed (e.g. ABCG2, SPP1), whereas some other genes designated as candidates based on their association with sheep and cattle dairy traits (e.g. LALBA, DGAT1A) were not associated with a detectable sweep signal. Few of the identified regions were coincident with QTL previously reported in sheep, although many of them corresponded to orthologous regions in cattle where QTL for dairy traits have been identified. Due to the limited number of QTL studies reported in sheep compared with cattle, the results illustrate the potential value of selection mapping to identify genomic regions associated with dairy traits in sheep.

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Uncoupling of PI3K from ErbB3 Impairs Mammary Gland Development but Does Not Impact on ErbB2-Induced Mammary Tumorigenesis

Cited by 21 publications

References 45 publications

ERBB3-Independent Activation of the PI3K Pathway in EGFR-Mutant Lung Adenocarcinomas

ERBB3-Independent Activation of the PI3K Pathway in EGFR-Mutant Lung Adenocarcinomas

Phenotypic and functional characterisation of the luminal cell hierarchy of the mammary gland

Application of Selection Mapping to Identify Genomic Regions Associated with Dairy Production in Sheep

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