Epidermal growth factor receptor (<scp>EGFR</scp>), <scp>HER</scp>2 and insulin‐like growth factor‐1 receptor (<scp>IGF</scp>‐1R) status in ovarian adult granulosa cell tumours

Higgins, Patricia A.; Brady, Aidan; Dobbs, Stephen; Salto-Tellez, Manuel; McCluggage, W. Glenn

doi:10.1111/his.12322

Cited by 10 publications

(5 citation statements)

References 20 publications

(36 reference statements)

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“…HER2 was positive in the majority of GCTs, and also in its phosphorylated form. These findings contradict the results of some of the earlier studies where GCTs were to be negative of HER2 19 , 21 – 24 . These mostly immunohistochemical studies involved the use of various methods and antibodies 19 , 21 .…”

Section: Discussioncontrasting

confidence: 99%

“…Previously, few studies have assessed the expression of HER2, HER3, and HER4 in GCTs, and found GCTs positive for HER3 and HER4 17 – 20 . The expression of HER2 in GCTs remains controversial; three studies revealed positive expression of HER2 in GCTs 17 , 18 , 20 , while five others did not 19 , 21 – 24 . The prognostic significances of HER2, HER3, and HER4 expressions and HER2 gene amplification in GCTs are unknown.…”

Section: Introductionmentioning

confidence: 99%

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HER2 and GATA4 are new prognostic factors for early‐stage ovarian granulosa cell tumor—a long‐term follow‐up study

et al. 2014

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Granulosa cell tumors (GCTs) carry a risk of recurrence also at an early stage, but reliable prognostic factors are lacking. We assessed clinicopathological prognostic factors and the prognostic roles of the human epidermal growth factor receptors (HER 2–4) and the transcription factor GATA4 in GCTs. We conducted a long-term follow-up study of 80 GCT patients with a mean follow-up time of 16.8 years. A tumor-tissue microarray was immunohistochemically stained for HER2–4 and GATA4. Expression of HER2–4 mRNA was studied by means of real time polymerase chain reaction and HER2 gene amplification was analyzed by means of silver in situ hybridization. The results were correlated to clinical data on recurrences and survival. We found that GCTs have an indolent prognosis, with 5-year disease-specific survival (DSS) being 97.5%. Tumor recurrence was detected in 24% of the patients at a median of 7.0 years (range 2.6–18 years) after diagnosis. Tumor stage was not prognostic of disease-free survival (DFS). Of the molecular prognostic factors, high-level expression of HER2, and GATA4, and high nuclear atypia were prognostic of shorter DFS. In multivariate analyses, high-level coexpression of HER2 and GATA4 independently predicted DFS (hazard ratio [HR] 8.75, 95% CI 2.20–39.48, P = 0.002). High-level expression of GATA4 also predicted shorter DSS (HR 3.96, 95% CI 1.45–12.57, P = 0.006). In multivariate analyses, however, tumor stage (II–III) and nuclear atypia were independent prognostic factors of DSS. In conclusion HER2 and GATA4 are new molecular prognostic markers of GCT recurrence, which could be utilized to optimize the management and follow-up of patients with early-stage GCTs.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HER2 and GATA4 are new prognostic factors for early‐stage ovarian granulosa cell tumor—a long‐term follow‐up study

et al. 2014

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“…In one series 75% of cases expressed at least one of the EGFR, HER3 or HER4 receptors [41]. EGFR and HER2 expression have been investigated in a small series of patients with adult GCT [42]. In 27 cases, EGFR immunohistochemistry was positive in 23 (74%) patients but all cases were HER2 negative [42].…”

Section: Novel Agentsmentioning

confidence: 99%

Stage I granulosa cell tumours: A management conundrum? Results of long-term follow up

Wilson

Fong

Mesnage

et al. 2015

Gynecologic Oncology

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“…Moreover, altered activation of the insulin-like growth factor 1 receptor and epidermal growth factor receptor pathways have been implicated in promoting adult human GCT progression (49,50), and this might be related to elevated gonadotropins in women during the perimenopausal period when adult type GCT occur most frequently (6). Specific targets of AKT include members of FOXO family of transcription factors that are highly conserved from Caenorhabditis elegans to man (51)(52)(53)(54).…”

mentioning

confidence: 99%

FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development

Liu

Ren

Pangas

et al. 2015

Molecular Endocrinology

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The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that Foxo1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the Foxo1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of FOXL2 and GATA4, and tumor formation.

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Epidermal growth factor receptor (EGFR), HER2 and insulin‐like growth factor‐1 receptor (IGF‐1R) status in ovarian adult granulosa cell tumours

Cited by 10 publications

References 20 publications

HER2 and GATA4 are new prognostic factors for early‐stage ovarian granulosa cell tumor—a long‐term follow‐up study

HER2 and GATA4 are new prognostic factors for early‐stage ovarian granulosa cell tumor—a long‐term follow‐up study

Stage I granulosa cell tumours: A management conundrum? Results of long-term follow up

FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development

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