Estrogen receptor-α mediates gene expression changes and growth response in ovarian cancer cells exposed to estrogen

O’Donnell, Amanda; MacLeod, Kenneth G.; Burns, David J.; Smyth, John F.; Langdon, Simon P.

doi:10.1677/erc.1.01039

Cited by 134 publications

(145 citation statements)

References 51 publications

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“…Of note, the majority of ovarian cancers express high levels of the folate receptor and also express the estrogen receptor. 19 The predominant staining pattern in the specimens is cytoplasmic yet there also appears to be slight nuclear staining. While some crossreactivity of mAb343 with an unrelated nuclear antigen cannot be excluded, it is also conceivable that FR may perform a nuclear regulatory function.…”

Section: Discussionmentioning

confidence: 91%

Folate receptor overexpression is associated with poor outcome in breast cancer

Hartmann

Keeney

Lingle

et al. 2007

Intl Journal of Cancer

219

134

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The high affinity folate receptor is a membrane-associated glycoprotein that is preferentially expressed in cancers of epithelial origin and rarely expressed in normal cells. We examined its expression pattern in breast cancer, utilizing a tissue microarray containing samples from 63 invasive breast cancers from women with divergent clinical outcomes. Thirty-three women comprised the poor outcome group with a median time to recurrence of 1.9 years. Thirty women, the good outcome group, were free of recurrence for a minimum of 7 years after diagnosis. The intensity of folate receptor staining was strongly correlated with outcome. There were two summary categories of staining intensity: weak (n 5 42) or strong (n 5 21). In the strong staining group, 17 of 21 women (81%) have recurred and their median survival is 2.4 years. In the weak staining group, 16 of 42 women (38%) have recurred. Their median survival is not estimable. After adjustment for tumor size, nodal status, ER status, adjuvant therapy, histology and tumor grade, strong staining for the folate receptor remained significantly associated with poor outcome, p < 0.001. Our work requires validation in a larger cohort, but supports the possibility of using folate receptor-targeted approaches in the management of breast cancer. ' 2007 Wiley-Liss, Inc.Key words: folate receptor; breast cancer; prognosis Folic acid and its reduced congeners are required for one carbon transfer reactions that are used in the biosynthesis of nucleotide bases, amino acids and other methylated compounds, and consequently, they are needed in larger quantities by proliferating cells. Physiological folates are transported into cells by either a low affinity reduced folate carrier (K m 5 10 25 M) or a high affinity folate receptor (K d 5 10 210 M). [1][2][3][4][5] The reduced folate carrier is ubiquitously expressed and constitutes the sole folate uptake pathway for most normal cells.The high affinity receptor is a glycosylphosphatidylinositolanchored membrane protein originally identified as a mAb-defined antigen in placenta and trophoblastic cells. It is rarely expressed or inaccessible in most normal cells. However, it is upregulated in select cancers of epithelial origin. 6 Distribution and binding studies of the high affinity folate receptor have shown high expression in the majority of ovarian cancers, and lesser degrees of positivity in kidney, breast, uterine and lung cancers. 6-10 Studies in ovarian cancer have shown an association between folate receptor overexpression and tumor aggressiveness. 7,[11][12][13] Studies of folate receptor expression in breast cancers have found varying results, depending on the techniques used and tissues analyzed. Ross et al. measured mRNA for the folate receptor and found levels to be elevated in five cancers when compared with normal breast specimens; however, the degree of elevation was 10-fold less than that seen in ovarian cancer. 10 Garin-Chesa et al. used a mouse monoclonal antibody LK26 to assess folate receptor expression in a variet...

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Section: Discussionmentioning

confidence: 91%

Folate receptor overexpression is associated with poor outcome in breast cancer

Hartmann

Keeney

Lingle

et al. 2007

Intl Journal of Cancer

219

134

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“…E2 is known to stimulate the growth of PE04 cells in a dose-dependent manner (21) and this stimulation could be reversed with either tamoxifen or pertuzumab (Fig. 5A).…”

Section: Pertuzumab Inhibits Hrgb1-activated Erk Phosphorylation and mentioning

confidence: 96%

“…In the panel of cell lines chosen for this study, we showed previously that only PE01, PE04, PE06, and SKOV3 cell lines have moderate to high levels of ERa, whereas the other lines have low or negligible levels (Table 1; ref. 21). Of these cell lines, only PE01, PE04, and PE06 (but not SKOV3) are growth modulated by estrogen (21).…”

Section: Pertuzumab Inhibits Hrgb1-activated Erk Phosphorylation and mentioning

confidence: 99%

“…21). Of these cell lines, only PE01, PE04, and PE06 (but not SKOV3) are growth modulated by estrogen (21). To explore potential interactions between estrogen signaling and pertuzumab action, we assessed the effects of pertuzumab on E2-modulated growth, cell signaling, cell cycle distribution, and apoptosis in PE04 cells and compared these actions with effects in the estrogen-unresponsive SKOV3 (ERa positive) cell line.…”

Section: Pertuzumab Inhibits Hrgb1-activated Erk Phosphorylation and mentioning

confidence: 99%

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Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling

Mullen

Cameron

Hasmann

et al. 2007

Molecular Cancer Therapeutics

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Pertuzumab (Omnitarg, rhuMab 2C4) is a humanized monoclonal antibody, which inhibits HER2 dimerization. Because it has shown some clinical activity in ovarian cancer, this study sought to identify predictors of response to this agent in a model of ovarian cancer. A panel of 13 ovarian cancer cell lines was treated with heregulin B1 (HRGB1) or transforming growth factor-A, and cell proliferation was assessed. Both agents increased cell number in the majority of cell lines studied, the response to both being similar (r = 0.83; P = 0.0004, Pearson test). HRGB1 stimulation could be partially reversed by pertuzumab in 6 of 13 cell lines, with complete reversal in PE04 and PE06 cells. Addition of pertuzumab to transforming growth factor-AÀstimulated cells produced growth inhibition in 3 of 13 cell lines (PE01, PE04, and PE06). The magnitude of HRGB1-driven growth stimulation correlated significantly with an increase in extracellular signal-regulated kinase 2 (P = 0.037) but not Akt (P = 0.99) phosphorylation. Such HRGB1-driven phosphorylation of extracellular signalregulated kinase 1/2 and Akt could be reduced with pertuzumab, accompanied by changes in cell cycle distribution. In cell lines responsive to pertuzumab, HRGB1-enhanced phosphorylation of HER2 (Tyr 877 ) was reduced. Estrogenstimulated changes in growth, cell cycle distribution, and signaling were reversed by pertuzumab, indicating crosstalk between HER2 and estrogen signaling. These data indicate that there is a subset of ovarian cancer cell lines sensitive to pertuzumab and suggest possible predictors of response to identify patients who could benefit from this therapy. Furthermore, we have identified an interaction between HER2 and estrogen signaling in this disease.

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“…4C). Genes that have previously been identified as being estrogen regulated in ovarian cancer (36) or known classical estrogen-regulated genes were investigated (37). Trastuzumab-treated and combination groups showed increases or decreases in expression of ERa target genes, appropriate to the expected activating or repressing action of ERa.…”

Section: Estrogen Receptor Expression and Downstream Gene Expression mentioning

confidence: 99%

Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies

Faratian

Zweemer

Nagumo

et al. 2011

Clinical Cancer Research

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Purpose: The aim of this study was to investigate the antitumor effects of HER2-directed combination therapy in ovarian cancer xenograft models to evaluate their potential. The combinations of trastuzumab and pertuzumab, and trastuzumab and aromatase inhibitor therapy were investigated.Experimental Design: The effects of trastuzumab, pertuzumab, and letrozole on growth response, apoptosis, morphology, and gene and protein expression were evaluated in the SKOV3 ovarian cancer cell line xenograft and a panel of five human ovarian xenografts derived directly from clinical specimens.Results: The combination of HER2-directed antibodies showed enhanced antitumor activity compared with single antibody therapy in the SKOV3 xenograft model. Apoptosis, morphology, and estrogenregulated gene expression were modulated by these antibodies in both spatial and temporal manners. A panel of ovarian cancer xenografts showed differential growth responses to the combination of trastuzumab and pertuzumab. High HER2 expression and increasing HER3 protein expression on treatment were associated with growth response. In trastuzumab-treated SKOV3 tumors, there was a change in tumor morphology, with a reduction in frequency of estrogen receptor alpha (ERa)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ERa in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ERa and downstream signaling targets were modulated by trastuzumab alone and in combination. Trastuzumab enhanced the responsiveness of SKOV3 xenografts to letrozole when given in combination.Conclusions: These data suggest that trastuzumab in combination with pertuzumab could be an effective approach in high HER2-expressing ovarian cancers and could also enhance sensitivity to endocrine therapy in ERa-positive ovarian cancer. Clin Cancer Res; 17(13); 4451-61. Ó2011 AACR.

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Estrogen receptor-α mediates gene expression changes and growth response in ovarian cancer cells exposed to estrogen

Cited by 134 publications

References 51 publications

Folate receptor overexpression is associated with poor outcome in breast cancer

Folate receptor overexpression is associated with poor outcome in breast cancer

Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling

Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies

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