Insulin-like growth factor-1 receptor (IGF-1R) expression does not predict for resistance to trastuzumab-based treatment in patients with Her-2/neu overexpressing metastatic breast cancer

Köstler, Wolfgang J.; Hudelist, Gernot; Rabitsch, Werner; Czerwenka, K.; Müller, Ruth Melinda; Singer, Christian F.; Zielinski, Christoph

doi:10.1007/s00432-005-0038-8

Cited by 46 publications

(42 citation statements)

References 46 publications

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“…Recently, IGF-IR was identified in B50% of breast carcinomas, 43 including ER-negative tumors, 44 although its presence was unrelated with prognosis or survival. 45,46 IGF-IR was identified in 36% of our series and rarely coincided with other growth factor receptors.…”

Section: Heterogeneity In Basal Breast Carcinomas E Lerma Et Almentioning

confidence: 60%

Immunohistochemical heterogeneity of breast carcinomas negative for estrogen receptors, progesterone receptors and Her2/neu (basal-like breast carcinomas)

et al. 2007

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Basal breast carcinomas triple negative for estrogen receptors, progesterone receptors and Her2/neu breast carcinomas are more aggressive than conventional neoplasms. We studied 64 cases with immunohistochemistry, using 23 antibodies, to characterize diverse pathological pathways. A basal cytokeratin was identified in 81% of tumors and vimentin was identified in 55%. The mean Ki67 index was 46% (range, 10-90%). Coincident expression of p50 and p65, which suggests an active nuclear factor-jB factor, was present in 13% of neoplasms. Epithelial growth factor receptor (EGFR), insulin-like growth factor-I receptor (IGF-IR) or c-kit (CD117) was identified in 77% of tumors. Loss of protein tyrosine phosphatase was found in 14%, whereas Akt activation was present in 28%. Several differences were identified between two subtypes of basal breast carcinomas: the pure variant (negative S-100 and actin) was more frequently associated with 'in situ carcinoma' (P ¼ 0.019) and pBad overexpression (P ¼ 0.098), whereas the myoepithelial variant (positive S-100 or actin) showed more frequent tumor necrosis (P ¼ 0.048), vimentin expression (P ¼ 0.0001), CD117 expression (P ¼ 0.001) and activated caspase-3 (P ¼ 0.089). IGF-IR could be as important as EGFR for the growth of these neoplasms. Basal cell carcinoma has at least two subtypes with distinct microscopic and immunohistochemical features.

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Section: Heterogeneity In Basal Breast Carcinomas E Lerma Et Almentioning

confidence: 60%

Immunohistochemical heterogeneity of breast carcinomas negative for estrogen receptors, progesterone receptors and Her2/neu (basal-like breast carcinomas)

et al. 2007

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“…20 However, a recent study of clinical samples has documented that IGF-1R status alone is insufficient to predict resistance to trastuzumab therapy. 21 This does not suggest that IGF-1R is not relevant to cancer maintenance, simply that receptor positivity is not necessarily indicative of dependence in a tumor or tumor cell line. Lack of a correlation between EGFR positivity and response to cetuximab has also been observed in clinical testing.…”

Section: Discussionmentioning

confidence: 99%

Synergy between an IGF-1R antibody and Raf/MEK/ERK and PI3K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells

et al. 2006

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“…Trastuzumab-induced growth inhibition was lost in breast cancer cells that overexpressed both insulin-like growth factor-I receptor (IGF-IR) and erbB2 (27). However, the expression of IGF-IR per se does not predict trastuzumab resistance in erbB2-overexpressing breast cancer patients (28), suggesting that activation of IGF-IR signaling may be more important than its expression for development of resistance to trastuzumab. Indeed, IGF-I signaling resulted in elevated expression of the p27 kip1 ubiquitin ligase SKP2, leading to decreased p27 kip1 and loss of growth arrest in the presence of trastuzumab (29).…”

Section: Introductionmentioning

confidence: 99%

Heterotrimerization of the Growth Factor Receptors erbB2, erbB3, and Insulin-like Growth Factor-I Receptor in Breast Cancer Cells Resistant to Herceptin

et al. 2010

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Primary and acquired resistance to the breast cancer drug trastuzumab (Herceptin) is a significant clinical problem. Here, we report enhanced activation of downstream signaling pathways emanating from the growth factor receptors erbB2, erbB3, and insulin-like growth factor-I receptor (IGF-IR) in trastuzumab-resistant breast cancer cells. Interactions between IGF-IR and erbB2 or erbB3 occur exclusively in trastuzumab-resistant cells, where enhanced erbB2-erbB3 interactions are also observed. Moreover, these three receptors form a heterotrimeric complex in resistant cells. erbB3 or IGF-IR knockdown by short hairpin RNA-mediated strategies upregulates p27 kip1 , inactivates downstream receptor signaling, and resensitizes resistant cells to trastuzumab. Our findings reveal a heterotrimer complex with a key role in trastuzumab resistance. On the basis of our results, we propose that trastuzumab resistance in breast cancer might be overcome by therapeutic strategies that jointly target erbB3, erbB2, and IGF-IR.

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Insulin-like growth factor-1 receptor (IGF-1R) expression does not predict for resistance to trastuzumab-based treatment in patients with Her-2/neu overexpressing metastatic breast cancer

Abstract: We conclude that IGF-1R expression is not a major predictor of the clinical efficacy of trastuzumab-based treatment in patients with Her-2/neu- overexpressing metastatic breast cancer.

Cited by 46 publications

References 46 publications

Immunohistochemical heterogeneity of breast carcinomas negative for estrogen receptors, progesterone receptors and Her2/neu (basal-like breast carcinomas)

Immunohistochemical heterogeneity of breast carcinomas negative for estrogen receptors, progesterone receptors and Her2/neu (basal-like breast carcinomas)

Synergy between an IGF-1R antibody and Raf/MEK/ERK and PI3K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells

Heterotrimerization of the Growth Factor Receptors erbB2, erbB3, and Insulin-like Growth Factor-I Receptor in Breast Cancer Cells Resistant to Herceptin

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