Estrogen and progesterone receptor expression in HPV-positive and HPV-negative cervical carcinomas

Kwaśniewska, Anna; Postawski, Krzysztof; Goździcka-Józefiak, Anna; Kwaśniewski, Wojciech; Grywalska, Ewelina; Zdunek, Małgorzata; Korobowicz, Elzbieta

doi:10.3892/or.2011.1256

Cited by 32 publications

(36 citation statements)

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“…In mouse models transgenic for HPV16 E6 and E7, our reports and others demonstrate that estrogen and ERα are critical for CxCa development (17,19,20). Consistent with the results presented here, decreased ERα levels in human cervical cancer cell lines and tumors and its correlation with invasiveness have been reported recently, although this was argued to reflect a lack of ERα action in late stages of CxCa (59,60). The more extensive analysis presented here shows that the progressive depletion of ERα expression occurs in the context of extensive, coordinated alterations in expression of estrogen- responsive genes (Fig.…”

Section: Discussionsupporting

confidence: 92%

Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling

Boon

Pyeon

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

226

213

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To study the multistep process of cervical cancer development, we analyzed 128 frozen cervical samples spanning normalcy, increasingly severe cervical intraepithelial neoplasia (CIN1-CIN3), and cervical cancer (CxCa) from multiple perspectives, revealing a cascade of progressive changes. Compared with normal tissue, expression of many DNA replication/repair and cell proliferation genes was increased in CIN1/ CIN2 lesions and further sustained in CIN3, consistent with high-risk human papillomavirus (HPV)-induced tumor suppressor inactivation. The CIN3-to-CxCa transition showed metabolic shifts, including decreased expression of mitochondrial electron transport complex components and ribosomal protein genes. Significantly, despite clinical, epidemiological, and animal model results linking estrogen and estrogen receptor alpha (ERα) to CxCa, ERα expression declined >15-fold from normalcy to cancer, showing the strongest inverse correlation of any gene with the increasing expression of p16, a marker for HPV-linked cancers. This drop in ERα in CIN and tumor cells was confirmed at the protein level. However, ERα expression in stromal cells continued throughout CxCa development. Our further studies localized stromal ERα to FSP1+, CD34+, SMA− precursor fibrocytes adjacent to normal and precancerous CIN epithelium, and FSP1−, CD34−, SMA+ activated fibroblasts in CxCas. Moreover, rank correlations with ERα mRNA identified IL-8, CXCL12, CXCL14, their receptors, and other angiogenesis and immune cell infiltration and inflammatory factors as candidates for ERα-induced stroma-tumor signaling pathways. The results indicate that estrogen signaling in cervical cancer has dramatic differences from ERα+ breast cancers, and imply that estrogen signaling increasingly proceeds indirectly through ERα in tumor-associated stromal fibroblasts.cervical cancer | HPV | estrogen | tumor microenvironment | stroma G lobally, cervical cancer (CxCa) is the second most common cancer in women, with >500,000 new cases each year, half of which are ultimately fatal (1). In the developed world, routine CxCa screening for abnormal cervical cytology, human papillomavirus (HPV), or both (2) has strongly reduced CxCa incidence, demonstrating the value of recognizing and removing early neoplasms (3). Such screening programs present a rare opportunity to study the sequential molecular changes in the development of a human cancer (4).CxCa development is related to infection with high-risk oncogenic HPVs, most prominently HPV16 and HPV18 (5-7). HPV oncoproteins E6 and E7 are best known for blocking tumor suppressor functions of p53 and Rb, respectively, but have numerous additional interaction partners (8-13). Most cervical HPV infections are cleared (14), but in a fraction of cases persistent infections lead to increasingly severe grades of dysplasia (cervical intraepithelial neoplasia grades 1, 2, and 3; CIN1, CIN2, CIN3) and ultimately to invasive cancer. Although the key steps of the carcinogenic process, HPV infection, progression to precancer, and invas...

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Section: Discussionsupporting

confidence: 92%

Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling

Boon

Pyeon

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

226

213

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“…Kwasniewska and coworkers reported a strong expression of ERα and PR in the stromal compartment of human CC specimens. Conversely, expression of both ERα and PR was decreased to undetectable levels in the tumour epithelium (Kwasniewska et al 2011).…”

Section: Maintenance Of Erα Expression In Tumour Stromamentioning

confidence: 99%

Functional association of oestrogen receptors with HPV infection in cervical carcinogenesis

Ramachandran¹

2017

Endocrine-Related Cancer

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Repeated parity and usage of oral contraceptives have demonstrated an increased risk of cervical cancer (CC) in HPV-infected women. These lifestyle observations raise the likelihood that oestrogens and HPV infection might act synergistically to affect cancers of the cervix. In vivo studies have indicated the requirement of oestrogens and ERα in the development of atypical squamous metaplasia followed by cervical intraepithelial neoplasia (CIN) I, II and III. CIN II and III are precancerous cervical lesions that can progress over time to CC as an invasive carcinoma. Recently, there has been evidence suggesting that ERα signalling in the tumour epithelium is a preliminary requisite during cancer initiation that is subsequently lost during tumorigenic progression. Conversely, continued expression of stromal ERα gains control over tumour maintenance. This review summarises the current information on the association between oestrogens and HPV infection in contributing to CC and the possibility of SERMs as a therapeutic option.

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“…Furthermore, other co-factors, which have been less thoroughly studied, also promote HCC development (3,4). Notably, a small percentage (10%) of HCCs develops independently of a persistent high-risk oncogenic HPV infection (5). The complex molecular mechanisms responsible for the development of HCCs thus remain partially unclear, and this hinders the identification of predictive markers for the early detection of malignancy development and the discovery of novel, effective therapies.…”

Section: Introductionmentioning

confidence: 99%

Bcl10 crucially nucleates the pro-apoptotic complexes comprising PDK1, PKCζ and caspase-3 at the nuclear envelope of etoposide-treated human cervical carcinoma C4-I cells

Chiarini

Liu

Armato

et al. 2015

International Journal of Molecular Medicine

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Abstract. Protein kinase (PK)Cζ signaling at various subcellular levels affects cell survival, differentiation, growth and/or apoptosis. However, the mechanisms modulating PKCζ activity at the nuclear membrane (NM) are not yet fully understood. Previously, we demonstrated that PKCζ interacts with the B-cell lymphoma 10 (Bcl10) protein at the NM of human cervical carcinoma (HCC) C4-I cells. In the present study, we aimed to further clarify the interactions between PKCζ, Bcl10 and other proteins co-immunoprecipitated from NMs isolated from untreated and etoposide (also known as VP-16; 2.0 µg/ml)-treated C4-I cells using biochemical and proteomics analyses. Aside from the Bcl10 protein, 3-phosphoinositide-dependent protein kinase-1 (PDK1) also co-immunoprecipitated with PKCζ from NMs of C4-I cells, indicating the assembly of a heterotrimeric complex, which increased with time in VP-16-exposed cells, as did the activity of PDK1-phosphorylated-PKCζ. In turn, PKCζ-phosphorylated-Bcl10 straddled an enlarged complex which comprised caspase-3. Subsequently, activity-enhanced caspase-3 cleaved and inactivated PKCζ. Finally, the suppression of Bcl10 using specific siRNA or lentiviral transduction prevented the increase in the PDK1•PKCζ association, the increase in the activity of PKCζ and caspase-3, as well as the caspase-3-mediated PKCζ proteolysis and inactivation from occurring at the NMs of the VP-16-exposed C4-I cells. Our observations provide evidence that Bcl10 acts as a pivotal pro-apoptotic protein which crucially nucleates complexes comprising PDK1, PKCζ and active caspase-3 at the NMs of VP-16-exposed C4-I cells. Hence, our data suggest that Bcl10 and PKCζ are potential therapeutic targets in the treatment of HCC. IntroductionThe disease with the second highest rate of mortality, for women, is human cervical carcinoma (HCC), which is prevalent in developing countries (1,2). The majority of HCCs derive from epithelial cells that have been persistently infected with high-risk oncogenic human papillomaviruses (HPVs), which express the E6 and E7 mRNAs, and proteins binding/neutralizing anti-oncogenic p53 and pRb. Furthermore, other co-factors, which have been less thoroughly studied, also promote HCC development (3,4). Notably, a small percentage (10%) of HCCs develops independently of a persistent high-risk oncogenic HPV infection (5). The complex molecular mechanisms responsible for the development of HCCs thus remain partially unclear, and this hinders the identification of predictive markers for the early detection of malignancy development and the discovery of novel, effective therapies.Proteomics and bioinformatics analysis have allowed researchers to identify differential protein expression patterns and the molecular mechanisms responsible for the development of HCC (6). A previous study identified a consensus of 66 proteins termed the 'central core of HCC protein expression̓ which was deduced from the proteomes of 6 HCC cell lines (not comprising the C4-I cell line); this differed from the proteomic profile...

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Estrogen and progesterone receptor expression in HPV-positive and HPV-negative cervical carcinomas

Cited by 32 publications

References 0 publications

Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling

Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling

Functional association of oestrogen receptors with HPV infection in cervical carcinogenesis

Bcl10 crucially nucleates the pro-apoptotic complexes comprising PDK1, PKCζ and caspase-3 at the nuclear envelope of etoposide-treated human cervical carcinoma C4-I cells

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