Distinct spatial expression patterns of AP-2alpha and AP-2gamma in non-neoplastic human breast and breast cancer

Friedrichs, Nicolaus; Jäger, Richard; Paggen, Ellen; Rudlowski, Christian; Merkelbach‐Bruse, Sabine; Schorle, Hubert; Buettner, Reinhard

doi:10.1038/modpathol.3800292

Cited by 48 publications

(83 citation statements)

References 23 publications

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“…Except for the breast, none of these control tissues showed positive staining for AP-2g. As described, 15 outer myoepithelial cells of normal ductuli lactiferi were immunopositive as were ductal invasive adenocarcinomas of the breast. Hence, AP-2g is not exclusively expressed in GCTs but can also be found in some tumors derived from somatic tissues.…”

Section: Distribution Of Ap-2 Immunostaining In Testicular Controls Amentioning

confidence: 64%

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Transcription factor AP‐2γ, a novel marker of gonocytes and seminomatous germ cell tumors

Pauls

Jäger

Weber

et al. 2005

Intl Journal of Cancer

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Most germ cell tumors (GCTs) arise from intratubular germ cell neoplasias (IGCNUs, also referred to as carcinoma in situ), which are thought to originate from a transformed fetal germ cell, the gonocyte. However, the nature of the molecular pathways involved in IGCNU formation remains elusive. Therefore, identification of novel oncofetal markers is an important prerequisite to further our understanding of the etiology of this tumor entity. In the present study, we show that in humans AP-2g is expressed in gonocytes at weeks 12-37 of gestation, indicating a role of this transcription factor in fetal germ cell development. AP-2g and c-KIT, a known target of AP-2 transcription factors, were coexpressed in gonocytes, making a direct regulation possible. With increasing differentiation of fetal testis, gradual downregulation of AP-2g from the 12th to 37th week of gestation was observed. Furthermore, AP-2g was expressed abundantly in 25/25 IGCNUs, 52/53 testicular seminomas, 10/10 metastatic seminomas, 9/9 extragonadal seminomas and 5/5 dysgerminomas. In embryonal carcinomas and choriocarcinomas, focal staining only was observed. Spermatocytic seminomas, teratomas and yolk sac tumors as well as normal adult testis and various control tissues were negative for AP-2g. The expression pattern of AP-2g, like that of other oncofetal markers, supports the model of a gonocytal origin of IGCNUs and germ cell tumors. Finally, our results provide the basis for applying AP-2g immunohistochemistry to the detection of GCT, a tumor entity with a steadily growing incidence in the male population worldwide. ' 2005 Wiley-Liss, Inc.Key words: AP-2g; gonocyte; neoplastic; seminoma; germ cell tumor The most abundant malignancies among men aged 17-45 are GCTs. 1 They comprise a heterogeneous group of neoplasms in terms of their histology, marker expression and age at manifestation. First described by Skakkebaek in 1972, the common precursor lesion of all GCTs, IGCNU (CIS, TIN, IGCN), arises from transformation of a gonocyte. 2,3 Markers commonly used for immunohistology, such as OCT3/4, PLAP and c-KIT, are expressed in gonocytes as well as IGCNUs and some stages of GCT, further supporting this model. TFAP2C belongs to a family of 5 closely related genes that are involved in the morphogenesis of craniofacial, urogenital, neural crest and placental tissues. 4 AP-2 transcription factors are believed to regulate the expression of several genes involved in cell growth and differentiation during development. 5 AP-2g is essential for mammalian embryonic development because embryonic trophectodermal cells fail to proliferate in AP-2g knockout mice. 6,7 In transgenic studies, overexpression of AP-2g impaired differentiation of epithelial cells of the mammary gland and the seminal vesicle. 8 Besides trophoblastic and neuroectodermal lineage, AP-2g can be detected in lung, testis and ovary. 9,10 In human tumors, AP-2g is upregulated in certain stages of melanoma 11 and breast cancer. 12,13 In the present study, we investigated the expression of AP-2...

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Section: Distribution Of Ap-2 Immunostaining In Testicular Controls Amentioning

confidence: 64%

“…15 Briefly, dewaxed tissue sections were microwave-pretreated prior to incubation with primary antibody. Sections were incubated overnight at 48C with a polyclonal rabbit anti-AP-2g antibody (1:500, H77; Santa Cruz Biotechnology, Heidelberg, Germany).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Transcription factor AP‐2γ, a novel marker of gonocytes and seminomatous germ cell tumors

Pauls

Jäger

Weber

et al. 2005

Intl Journal of Cancer

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“…63 In immunohistochemical studies using a large number of patient samples, Pellikainen et al 14 observed that the HER-2 2 /AP-2 1 patients had the best prognosis for recurrence-free survival while the worst prognosis was seen with HER-2 1 /AP-2 2 patients. In related studies, Friedrichs et al 64 observed distinct patterns of AP-2a and AP-2g spatial expression in nonneoplastic breast and breast cancer. Moreover, high expression of AP-2a correlated with high ER expression, better differentiation, and better survival of patients.…”

Section: Discussionmentioning

confidence: 99%

Inefficient proteasomal‐degradation pathway stabilizes AP‐2α and activates HER‐2/neu gene in breast cancer

Wang

Hung

et al. 2005

Intl Journal of Cancer

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HER-2/neu proto-oncogene is overexpressed in about one fourth of human breast cancers. AP-2 transcription factors bind to the HER-2/neu gene promoter and activate its expression. In a striking concurrence, anomalous abundance of AP-2a protein or its homolog AP-2c is also detected with HER-2/neu protein in mammary tumor-derived cell lines. This suggests that the deregulation of AP-2 is the preceding pathogenic event and probably the pivotal one in this type of mammary carcinogenesis. We examined the process of AP-2a gene expression in mammary carcinoma cell lines to identify where the aberration had occurred. We found no amplification of the AP-2a gene. Its promoter was marginally upregulated; however, it did not significantly increase the mRNA levels. When the AP-2a protein was examined, a remarkable stability was seen in breast cancer cell lines MDA-MB-453 and SK-BR-3, with a half-life of over 30 hr. This is sharply higher than the approximate 1 hr observed in mammary epithelial cell line MCF-10A and murine cell line NIH 3T3. Treatment of MCF-10A and NIH 3T3 cells with the proteasome inhibitor MG-132 showed that AP-2a was ubiquitinated and its level significantly increased. Moreover, this increase was accompanied by elevated levels HER-2/neu protein. In contrast, weaker ubiquitination of AP-2a was seen in MDA-MB-453 and SK-BR-3 cancer cells, and MG-132 treatment did not raise the AP-2a level any further. These results uncover that unusual stability is the main mechanism that raises the levels of AP-2 proteins, and in addition, provide the first clue that defective ubiquitin-dependent proteasomal-degradation pathway is possibly the prime cause that affects the HER-2/neu gene and culminates in breast cancer. ' 2005 Wiley-Liss, Inc.

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“…Two other studies using different polyclonal AP-2γ antibodies failed to find a link with outcome. One study focused on patients with early-stage disease treated with lumpectomy [15] and in the second study the commercial antibody employed apparently only stained the myoepithelial compartment [37]. In contrast, using gene expression profiling, TFAP2C mRNA expression was associated with advancing clinical grade (p < 0.002 [17]).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti‐hormone therapy and reduced patient survival

Gee

Eloranta²,

Ibbitt³

et al. 2008

The Journal of Pathology

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The AP-2γ transcription factor encoded by the TFAP2C gene is a member of a family of homologous DNA binding proteins that play essential roles during vertebrate embryogenesis but show a restricted pattern of expression in the adult. Elevated expression of the AP-2α and AP-2γ family members has been associated with a number of neoplasms, particularly breast cancer. Here we present an exploratory immunohistochemical study of an archival primary breast tumour series (n = 75) with parallel clinicopathological data using a new, well-characterized antibody to AP-2γ . Heterogeneous, exclusively nuclear expression of AP-2γ was found in the epithelial and myoepithelial compartments of normal breast and within tumour epithelial cells. In the breast cancer series, the most notable association was a correlation between elevated levels of AP-2γ and shortened patient survival (p = 0.0009 * ). This relationship was also conserved in ER-positive and ErbB2-negative patients; sub-groups generally considered to have a relatively good prognosis. When patient data for survival and duration of treatment response on anti-hormone therapy were examined by multivariate analysis, AP-2γ was revealed in this study to be an independent predictor of outcome for both survival (p = 0.005) and response to anti-hormone therapy (p = 0.046). Studies using in vitro models confirmed that while tamoxifen response is associated with lower levels of AP-2γ , acquisition of resistance to this and other anti-hormone measures (eg faslodex or oestrogen deprivation) is associated with high levels of nuclear AP-2γ . Together these data suggest that elevated tumour AP-2γ expression can contribute to the failure of cells to growth arrest following anti-hormone treatment and lead to sustained growth and poorer patient outcome.

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Distinct spatial expression patterns of AP-2alpha and AP-2gamma in non-neoplastic human breast and breast cancer

Cited by 48 publications

References 23 publications

Transcription factor AP‐2γ, a novel marker of gonocytes and seminomatous germ cell tumors

Transcription factor AP‐2γ, a novel marker of gonocytes and seminomatous germ cell tumors

Inefficient proteasomal‐degradation pathway stabilizes AP‐2α and activates HER‐2/neu gene in breast cancer

Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti‐hormone therapy and reduced patient survival

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