Cooperative Interactions of HER-2, HPV-16 Oncoproteins in the Malignant Transformation of Human Mammary Epithelial Cells

Ignatoski, Kathleen M. Woods; Dziubinski, Michele; Ammerman, Cheryl A.; Ethier, Stephen P.

doi:10.1593/neo.05106

Cited by 31 publications

(33 citation statements)

References 40 publications

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“…Furthermore, ErbB2 mRNA levels were not altered in the presence of HPV16 E6 (Figure 5a). Increase in ErbB2 transgene levels in HPV16 E6 and E7 expressing human mammary epithelial cells has been reported (Gewin et al, 2004;Woods Ignatoski et al, 2005). Thus HPV16 E6 might upregulate ErbB2 expression through translational as well as post-translational modifications and the detailed molecular mechanisms underlying postconfluent regulation of ErbB2 by E6-targeted proteins should be addressed further.…”

Section: Chxmentioning

confidence: 96%

HPV16 E6-mediated stabilization of ErbB2 in neoplastic transformation of human cervical keratinocytes

Narisawa‐Saito¹,

Handa²,

Yugawa³

et al. 2006

Oncogene

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Whether ErbB2 receptor tyrosine kinase contributes to cervical cancer is controversial. We have examined the effects of E6 and E7 genes of human papillomaviruses type 16 (HPV-16) on ErbB2 expression in primary human cervical keratinocytes (HCK) immortalized with hTERT (HCK1T). In E6-positive cells (HCK1T-E6 and HCK1T-E6E7), ErbB2 expression levels increased with the cell density. HCK1T-E6E7 showed impaired contact inhibition and anchorage-independent growth in soft agar which were abrogated with introduction of ErbB2-specific short hairpin RNA (shRNA) or an ErbB2 specific inhibitor AG825. Furthermore, increased ErbB2 expression was also observed in HPV16 positive cervical cancer cell lines and this was diminished by introduction of HPV16E6-or E6AP-shRNA. At post-confluence cell densities, ErbB2 protein was stabilized in the presence of E6 whereas increased ErbB2 expression was not obvious with E6 mutants incapable of degrading p53. Furthermore, introduction of p53-shRNA to HCK1T resulted in increased ErbB2 protein stability, indicating possible ErbB2 regulation through p53. Finally, we showed that tumor formation of ErbB2-shRNA introduced SiHa cells were almost abolished. Taken together, these data indicate an important role of ErbB2 regulation by HPV16 E6 in oncogenic transformation of human cervical keratinocytes.

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Section: Chxmentioning

confidence: 96%

HPV16 E6-mediated stabilization of ErbB2 in neoplastic transformation of human cervical keratinocytes

Narisawa‐Saito¹,

Handa²,

Yugawa³

et al. 2006

Oncogene

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“…The MCF10A human mammary epithelial cell line and SUM44 breast cancer cell line were cultured as described previously (Forozan et al, 1999;Woods Ignatoski et al, 2005). MCF10Lsm1 cells were cultured in MCF10A medium with the antibiotic blasticidin (10 mg/ml) and without insulin.…”

Section: Cell Culture Conditionsmentioning

confidence: 99%

“…Cell lysis and protein quantification were performed as described previously (Woods Ignatoski et al, 2005). For IRS-1 immunoprecipitation, cell lysate (1 mg) was incubated with 2 mg/mg of IRS-1 antibody for 2 h at 41C followed by incubation with protein A/G agarose beads (Sigma) for 1 h at 41C.…”

Section: Immunoprecipitation and Western Blotsmentioning

confidence: 99%

Transforming function of the LSM1 oncogene in human breast cancers with the 8p11–12 amplicon

et al. 2006

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Amplification of the 8p11-12 region occurs in 15-20% of breast cancers, but the driving oncogene at this locus has yet to be definitively identified. We mapped the 8p11-12 amplicon in breast cancer cell lines and primary human breast cancers and identified the candidate oncogene human Sm-like protein (hLsm1, LSM1) based on increases in copy number and expression level relative to human mammary epithelial cells. To examine the oncogenic role of LSM1, we overexpressed this gene in MCF10A mammary epithelial cells and inhibited its production in the SUM44 breast cancer cell line, which has a natural amplification and overexpression of LSM1. Our data confirmed that LSM1 is an oncogene from the 8p11-12 amplicon by showing that hLsm1 overexpression induced growth factor-independent proliferation and soft agar colony formation in MCF10A cells, and hLsm1 inhibition in SUM44 cells dramatically reduced soft agar growth. Little is known about hLsm1 function other than its involvement in mRNA degradation; therefore, we used expression microarray analysis to investigate how hLsm1 affects cell transformation in MCF10A and SUM44 cells. We identified numerous genes altered following hLsm1 overexpression common to SUM44 breast cancer cells that play important roles in cell cycle regulation, cell proliferation and other cancer-promoting processes. Future work will continue to characterize these important changes to achieve a more complete understanding of the mechanism of hLsm1's effect on cancer progression.

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“…Hematoxylin and eosin (H&E) histology, and immunohistochemical analyses for ErbB-2 and b-catenin of tumors derived from the transgenic mice cells were performed as previously described in ref. 15 except that anti-b-catenin mAb (clone 14, Bio/Can Scientific) was used for the immunohistochemistry analysis.…”

Section: Methodsmentioning

confidence: 99%

“…14 Recently, Woods Ignatoski et al reported that E6/E7 of HPV type 16 and ErB-2 cooperate with endogenous epidermal growth factor-receptor (EGF-R/ErbB1) to fully transform human breast immortalized cell line, MCF-10A. 15 Our group has developed a new in vitro model to study the effects of E6/E7 of HPV type 16 and ErbB-2 in human normal oral epithelial (NOE) cells. Using this model, we demonstrated that E6/E7 cooperates with ErbB-2 receptor to induce cellular transformation of NOE via the conversion of b-catenin from a cell-adhesion molecule to a potential transcriptional regulator.…”

Section: Introductionmentioning

confidence: 99%

ErbB-2 Receptor Cooperates with E6/E7 Oncoproteins of HPV Type 16 in Breast Tumorigenesis

Yasmeen

Bismar²,

Dekhil³

et al. 2007

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/4949 KEY woRDsBreast tumorigenesis, transgenic mice, ErbB-2 and E6/E7 of high-risk HPV ACKnowlEDGEMEnTsWe are grateful to Drs G. Batist, M. AlaouiJamali and Foulkes for their support of this work. We are thankful to Dr. A. Darnel for his critical reading of the manuscript. We also thank Dr. T. Li-Qun and G. Mousavi for their technical assistance. This work is supported by the Canadian Institutes for Health Research (Ala-Eddin Al Moustafa) and the National Colorectal Cancer Campaign (Ala-Eddin Al Moustafa and Tarek A. Bismar). ABsTRACTThe ErbB-2 receptor is over-expressed in roughly 30% of human breast cancers. Moreover, approximately 50% of breast cancers are positive for high-risk human papillomaviruses (HPVs). Recently, we reported that ErbB-2 cooperates with E6/E7 oncoproteins of HPV type 16 to induce neoplastic transformation of human normal oral epithelial cells. We also demonstrated that E6/E7 of HPV type 16 converts noninvasive breast cancer cells to an invasive form. In order to investigate the effect of ErbB-2/E6/E7 cooperation in breast carcinogenesis, we generated double transgenic mice carrying ErbB-2 and E6/E7 of HPV type 16 under mouse mammary tumor virus (MMTV) and human keratin 14 promoters, respectively. Within six months, these double transgenic mice developed large and extensive invasive breast cancer in comparison to ErbB-2 or E6/E7 singly transgenic mice. Histological analysis of ErbB-2/ E6/E7 transgenic mice tumors showed the presence of invasive breast carcinomas. However, the breast tissues from ErbB-2 and E6/E7 transgenic mice showed only in-situ cancer and normal mammary phenotype, respectively. In parallel, we examined the cooperation effect of ErbB-2 and E6/E7 in the human breast cancer cell line, BT20; in comparison to ErbB-2 and E6/E7 alone as well as wild type cells, we found that ErbB 2/E6/E7 together stimulate colony formation and cell migration in the BT20 cell line. Furthermore, we found that b-catenin is constitutively phosphorylated by c-Src and consequently trans-located to the nucleus in ErbB-2/E6/E7-breast cancer cells. These findings provide evidence that the ErbB-2 receptor cooperates with high-risk HPVs in breast tumorigenesis via b-catenin activation.

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Cooperative Interactions of HER-2, HPV-16 Oncoproteins in the Malignant Transformation of Human Mammary Epithelial Cells

Cited by 31 publications

References 40 publications

HPV16 E6-mediated stabilization of ErbB2 in neoplastic transformation of human cervical keratinocytes

HPV16 E6-mediated stabilization of ErbB2 in neoplastic transformation of human cervical keratinocytes

Transforming function of the LSM1 oncogene in human breast cancers with the 8p11–12 amplicon

ErbB-2 Receptor Cooperates with E6/E7 Oncoproteins of HPV Type 16 in Breast Tumorigenesis

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