Ligand‐independent epidermal growth factor receptor hyperactivation increases sebaceous gland size and sebum secretion in mice

Dahlhoff, Maik; Angelis, Martin Hrabě de; Wolf, Eckhard; Schneider, Marlon R.

doi:10.1111/exd.12219

Cited by 20 publications

(21 citation statements)

References 25 publications

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“…Furthermore, overexpression of MYC in the skin of transgenic mice results in SG enlargement (55,56). In addition, increased Myc expression was previously detected in the skin of Dsk5 mice, a mutant line expressing a constitutively active EGFR that also exhibits enlarged SGs (57). To evaluate a possible involvement of Myc in the SG phenotype of K14-EPGN mice, we therefore measured its expression by qRT-PCR.…”

Section: Sox9-positive Cells (Seementioning

confidence: 99%

Overexpression of Epigen during Embryonic Development Induces Reversible, Epidermal Growth Factor Receptor-Dependent Sebaceous Gland Hyperplasia

Dahlhoff¹,

Frances

Kloepper

et al. 2014

Molecular and Cellular Biology

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fThe epidermal growth factor receptor (EGFR) system is a key regulator of epithelial development and homeostasis. Its functions in the sebaceous gland (SG), however, remain poorly characterized. In this study, using a transgenic mouse line with tissue-specific and inducible expression of the EGFR ligand epigen, we showed that increased activation of the EGFR in skin keratinocytes results in enlarged SGs and increased sebum production. The phenotype can be reverted by interrupting transgene expression and is EGFR dependent, as gland size and sebum levels return to normal values after crossing to the EGFR-impaired mouse line Wa5. Intriguingly, however, the SG enlargement appears only if EGFR activation occurs before birth. Importantly, the enlarged sebaceous glands are associated with an increased expression of the transcription factor MYC and of the transmembrane proteins LRIG1, an established negative-feedback regulator of the EGFR/ERBB tyrosine kinase receptors and a stem cell marker. Our findings identify EGFR signaling as a major pathway determining SG activity and suggest a functional relationship between the EGFR/ERBB system and MYC/LRIG1 in the commitment of stem cells toward specific progenitor cell types, with implications for our understanding of their role in tissue development, homeostasis, and disease.

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Section: Sox9-positive Cells (Seementioning

confidence: 99%

Overexpression of Epigen during Embryonic Development Induces Reversible, Epidermal Growth Factor Receptor-Dependent Sebaceous Gland Hyperplasia

Dahlhoff¹,

Frances

Kloepper

et al. 2014

Molecular and Cellular Biology

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“…The pathogenic roles of the sebaceous gland in AfE by EGFRI are still controversial. Since an increase in the sebum levels and enlarged sebaceous glands were observed in Dsk5 mice, a mutant line in which EGFR is constitutively activated ligand‐independently and a decrease in the sebum production has been assumed in EGFRI‐treated patients. However, higher SSL levels in the EGFRI‐treated patients with AfE than in those without AfE has been reported recently .…”

Section: Discussionmentioning

confidence: 99%

Instrumental evaluation sensitively detects subclinical skin changes by the epidermal growth factor receptor inhibitors and risk factors for severe acneiform eruption

Kikuchi

Nozawa

Yamazaki

et al. 2018

The Journal of Dermatology

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Epidermal growth factor receptor inhibitors (EGFRI), EGFR tyrosine kinase inhibitors (TKI) and anti‐EGFR antibodies commonly develop skin toxicities including acneiform eruption (AfE). However, precise skin changes and risk factors for severe AfE are still unclear. The objective of the current study was elucidation of the useful parameters for early and sensitive detection of the skin changes by EGFRI. Transepidermal water loss (TEWL), skin surface hydration, skin surface lipid levels and erythema/melanin index were serially measured for 2 weeks in 19 EGFR‐TKI afatinib/erlotinib‐treated patients and for 8 weeks in 20 anti‐EGFR antibody cetuximab‐treated patients. The TEWL levels of the cheek in the patients who developed AfE of grade 2 and more (AfE ≥ Gr2) were already elevated at 7 days after the initiation of afatinib/erlotinib therapy compared with those before therapy as well as in patients with grade 1 or less (AfE ≤ Gr1). In patients treated with cetuximab, the skin surface hydration on the cheek in AfE ≥ Gr2 patients significantly decreased compared with that of AfE ≤ Gr1 patients at the 2nd and 6th week. Baseline skin surface lipid levels and erythema index on the cheek of patients with AfE ≥ Gr2 were significantly higher than those with AfE ≤ Gr1. The small sample size of the present study, especially for logistic regression analysis, is a limitation. In conclusion, instrumental evaluation declared rapid inflammatory changes of the skin by EGFRI and elucidated oily skin as a risk for severe AfE.

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“…Sebaceous gland dysfunction appears to contribute most to the eruptions, because the acneiform rash develops in the early phase of egfri treatment 5,7 . Recently, a study in a mouse model demonstrated increased secretion of sebum from the sebaceous glands because of constant egfr activation 8,9 . Further nonclinical studies confirmed that activation of egfr induces sebaceous gland enlargement and sebocyte proliferation by upregulating the transcription c-Myc 10-12 , indicating a pivotal role for egfr signalling in maintaining the size, cell number, and sebum activity of sebaceous glands.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Sebum Lipid Composition and the Development of Acneiform Rash before and after Administration of egfr Inhibitor

et al. 2015

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Treatment with an epidermal growth factor receptor inhibitor (egfri) in patients having non-small-cell lung cancer can cause frequent and diverse skin toxicities, an acneiform rash being one of the commonest. Although the exact pathophysiology of this rash and its development mechanisms remain unknown, investigators have noted that egfriinduced skin toxicity might be partly associated with sebaceous gland function. Sebum is composed mainly of the lipids squalene (sq), wax ester (we), triglyceride, free fatty acid, and cholesterol, which are secreted mostly from the sebaceous glands and by keratinocytes. We therefore investigated the lipid composition of sebum before and after administration of egfri and whether sebum composition was associated with the development of acneiform rash. To investigate any associated changes in sebum gland activity, we focused especially on alterations in the amounts of sq and we, which are secreted solely from the sebaceous glands.In contrast to our expectations, we observed no substantial changes in the lipid composition of sebum before and after administration of egfri. Composition varies with the individual; however, the proportion of sq and we derived from the sebaceous glands was significantly lower in regions that did not develop acneiform rash than in regions that did. Our results suggest that development of an acneiform rash after administration of egfri could be related to sebaceous gland activity. Measurement of the lipid composition of sebum before therapy with egfri might predict which patients will be prone to acneiform rash.

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Ligand‐independent epidermal growth factor receptor hyperactivation increases sebaceous gland size and sebum secretion in mice

Cited by 20 publications

References 25 publications

Overexpression of Epigen during Embryonic Development Induces Reversible, Epidermal Growth Factor Receptor-Dependent Sebaceous Gland Hyperplasia

Overexpression of Epigen during Embryonic Development Induces Reversible, Epidermal Growth Factor Receptor-Dependent Sebaceous Gland Hyperplasia

Instrumental evaluation sensitively detects subclinical skin changes by the epidermal growth factor receptor inhibitors and risk factors for severe acneiform eruption

Analysis of Sebum Lipid Composition and the Development of Acneiform Rash before and after Administration of egfr Inhibitor

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