Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

Jones, Robert A.; Campbell, Craig I.; Gunther, Edward J.; Chodosh, Lewis A.; Petrik, Jim; Khokha, Rama; Moorehead, Roger A.

doi:10.1038/sj.onc.1209955

Cited by 119 publications

(152 citation statements)

References 45 publications

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“…We have also found that some advanced IGF-IR-induced tumors resemble Wnt pathway initiated tumors and contain areas with considerable stromal elements and cytokeratin 5 and 14 positive cells (Jones et al, 2007). However, we have yet to observe tumors that would be classified histologically as spindle-cell tumors.…”

Section: Igf-ir Independence Is Accompanied By An Emtmentioning

confidence: 81%

“…We have shown earlier that IGF-IR overexpression in MTB-IGFIR mice results in the rapid development of multiple mammary tumors (Jones et al, 2007). In this paper, we describe the consequence of eliminating IGF-IR transgene expression in established mammary tumors.…”

Section: Introductionmentioning

confidence: 89%

“…To address this, we used primers that detect the human IGF-IR cDNA sequence. Importantly, these primers have been used to distinguish mice carrying the IGF-IR transgene and wild-type mice and thus do not amplify the endogenous mouse IGF-IR transcript (Jones et al, 2007). Both primary and epithelial DITs expressed high levels of human IGF-IR, whereas spindle DITs expressed low levels of human IGF-IR as determined by RT-PCR (Figure 4m).…”

Section: Doxycycline-independent Growth Is Associated With Igf-ir-depmentioning

confidence: 99%

“…We have reported earlier that MTB-IGF-IR tumors contain increased levels of downstream IGF-IR signaling molecules including the phosphorylated forms of Akt, Erk1/Erk2, and Stat3 compared with normal mammary tissue (Jones et al, 2007). To determine whether escape from IGF-IR dependence was associated with alterations in these pathways, we examined their protein expression levels in primary tumors and DITs (Figure 6b).…”

Section: Igf-ir Independence Is Accompanied By An Emtmentioning

confidence: 99%

“…Overexpression of IGF-I (Hadsell et al, 2000) or IGF-II (Bates et al, 1995;Pravtcheva and Wise, 1998) in the mammary epithelium results in tumor development, albeit with long latency. Recently, mammary specific overexpression of a constitutively active IGF-IR (Carboni et al, 2005) or wildtype IGF-IR (Jones et al, 2007) has been shown to induce rapid tumor formation by 2 months of age.…”

Section: Introductionmentioning

confidence: 99%

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Reversibility and recurrence of IGF-IR-induced mammary tumors

et al. 2009

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Section: Igf-ir Independence Is Accompanied By An Emtmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 89%

Section: Doxycycline-independent Growth Is Associated With Igf-ir-depmentioning

confidence: 99%

Section: Igf-ir Independence Is Accompanied By An Emtmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reversibility and recurrence of IGF-IR-induced mammary tumors

et al. 2009

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Effect of metformin on survival outcomes in diabetic patients with triple receptor‐negative breast cancer

Bayraktar

Hernadez-Aya

Lei

et al. 2011

Cancer

160

143

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Background Recent observational studies have shown that metformin use in diabetics decreases both cancer incidence and mortality. Metformin use is also independently predictive of pathologic complete response. We explored the association between metformin use and survival outcomes in patients with triple receptor-negative breast cancer (TNBC) receiving adjuvant chemotherapy. Methods The Breast Cancer Management System database of The University of Texas M.D. Anderson Cancer Center identified 1448 women who received adjuvant chemotherapy for TNBC between 1995 and 2007. Patients were categorized by diabetes status and metformin use. Kaplan-Meier product limit method was used to calculate distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS). Cox proportional hazards models were fit to determine the association between metformin use and survival outcomes. Results Our study cohort consisted of 63 diabetic patients taking metformin, 67 diabetic patients not taking metformin, and 1318 non-diabetic patients. Patients in the diabetic groups tended to be older (P=0.005); more diabetic patients were postmenopausal (P=0.0007), black (P=0.0001), and obese (P < 0.0001). At a median follow-up of 62 months, there were no significant differences in 5-year DMFS (P=0.23), RFS (P=0.38), and OS (P=0.58) between the three groups. Compared to the metformin group, patients who did not take metformin (Hazard ratio [HR]=1.63; 95% CI:0.87 to 3.06; P=0.13) and nondiabetics (HR=1.62; 95% CI:0.97 to 2.71; P=0.06) tended to have a higher risk of distant metastases. Conclusion Our findings suggest that metformin use during adjuvant chemotherapy does not significantly impact survival outcomes in diabetic patients with TNBC.

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Integrative analysis of copy number and gene expression data identifies potential oncogenic drivers that promote mammary tumor recurrence

Jones

Moorehead

2019

Genes Chromosomes & Cancer

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Tumor recurrence represents a significant clinical challenge in the treatment and management of breast cancer. To investigate whether copy number aberrations (CNAs) facilitate the re‐emergence of tumor growth from residual disease, we performed array comparative genomic hybridization on primary and recurrent mammary tumors from an inducible mouse model of type‐I insulin‐like growth factor receptor driven breast cancer. This genome‐wide analysis revealed primary and recurrent tumors harbored distinct CNAs with relapsed tumors containing an increased number of gene‐level gains and losses. Remarkably, high‐level CNAs detected in primary tumors were largely devoid of annotated cancer genes while the vast majority of recurrent tumors harbored at least one CNA containing a known oncogene or tumor suppressor. Specifically, 38% of recurrent tumors carried gains at 6qA2 and 9qA2 which encode the Met and Yap1 oncogenes, respectively. The most frequent CNA, occurring in 63% of recurrent tumors, was a focal deletion at 4qC5 involving the Cdkn2a/b tumor suppressor genes. Integrative analysis revealed positive correlations between gene copy number and mRNA expression suggesting Met, Yap1, and Cdkn2a/b may serve as potential drivers that promote tumor recurrence. Accordingly, cross‐species analysis revealed gene‐level murine CNAs were present in a subset of human breast cancers with high MET and YAP1 mRNA predictive of decreased relapse‐free survival in basal‐like breast cancers. Together, these findings indicate that tumor recurrence is facilitated by the acquisition of CNAs with oncogenic potential and provide a framework to dissect the molecular mechanisms that mediate tumor escape from dormancy.

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Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

Cited by 119 publications

References 45 publications

Reversibility and recurrence of IGF-IR-induced mammary tumors

Reversibility and recurrence of IGF-IR-induced mammary tumors

Effect of metformin on survival outcomes in diabetic patients with triple receptor‐negative breast cancer

Integrative analysis of copy number and gene expression data identifies potential oncogenic drivers that promote mammary tumor recurrence

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