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Association between insulin-like growth factor-1 receptor (IGF1R) negativity and poor prognosis in a cohort of women with primary breast cancer.

Aaltonen KE, Rosendahl AH, Olsson H, Malmström P, Hartman L, Fernö M - BMC Cancer (2014)

Bottom Line: We found that lower IGF1R expression was associated with worse prognosis for tamoxifen treated, postmenopausal women (HR = 0.70, 95% CI = 0.52 - 0.94, p = 0.016).The lack of co-activation of downstream markers (p-mTOR and p-S6rp) in the IGF1R pathway suggested that the prognostic effect was not due to complete activation of this pathway.Thus, no evidence could be found for a compensatory function of IGF1R signaling in the investigated cohorts.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE-223 81 Lund, Sweden. kristina.aaltonen@med.lu.se.

ABSTRACT

Background: Resistance towards endocrine therapy is a great concern in breast cancer treatment and may partly be explained by the activation of compensatory signaling pathways. The aim of the present study was to investigate if the insulin-like growth factor-1 receptor (IGF1R) signaling pathway was activated or deregulated in breast cancer patients and to explore if any of the markers were prognostic, with or without adjuvant tamoxifen. This signaling pathway has been suggested to cause estrogen independent cell growth and thus contribute to resistance to endocrine treatment in estrogen receptor (ER) positive breast cancer.

Methods: The protein expression of IGF1R, phosphorylated Mammalian Target of Rapamycin (p-mTOR) and phosphorylated S6 ribosomal protein (p-S6rp) were investigated by immunohistochemistry using tissue microarrays in two patient cohorts. Cohort I (N = 264) consisted of mainly postmenopausal women with stage II breast cancer treated with tamoxifen for 2 years irrespective of ER status. Cohort II (N = 206) consisted of mainly medically untreated, premenopausal patients with node-negative breast cancer. Distant disease-free survival (DDFS) at 5 years was used as end-point for survival analyses.

Results: We found that lower IGF1R expression was associated with worse prognosis for tamoxifen treated, postmenopausal women (HR = 0.70, 95% CI = 0.52 - 0.94, p = 0.016). The effect was seen mainly in ER-negative patients where the prognostic effect was retained after adjustment for other prognostic markers (adjusted HR = 0.49, 95% CI = 0.29 - 0.82, p = 0.007). Expression of IGF1R was associated with ER positivity (p < 0.001) in the same patient cohort.

Conclusions: Our results support previous studies indicating that IGF1R positivity reflects a well differentiated tumor with low metastatic capacity. An association between lack of IGF1R expression and worse prognosis was mainly seen in the ER-negative part of Cohort I. The lack of co-activation of downstream markers (p-mTOR and p-S6rp) in the IGF1R pathway suggested that the prognostic effect was not due to complete activation of this pathway. Thus, no evidence could be found for a compensatory function of IGF1R signaling in the investigated cohorts.

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Distribution of staining intensities for the experimental markers.
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Fig3: Distribution of staining intensities for the experimental markers.

Mentions: The distribution of staining intensities for the different experimental markers is illustrated in Figure 3. For both cohorts, the association between IGF1R cytoplasm intensity and tumor characteristics can be found in Table 1. Data from IGF1R membrane staining gave comparable results and can be found in detail in Additional file 1 together with data from p-mTOR and IGF1R staining. Notable is that in Cohort I there was very strong evidence of a positive association between ER/PgR positivity and a high expression of IGF1R (p < 0.001). High p-S6rp was strongly associated with hormone receptor positivity (p < 0.001 for both ER and PgR). For p-mTOR there was very strong evidence for a positive association with Ki67 expression (p < 0.001), and slight evidence for an association with ER positivity (p = 0.068). In Cohort II, high p-mTOR expression was associated with ER positivity (p = 0.014) and higher age (p = 0.026), whereas it was negatively associated with Ki67 expression (p = 0.010). p-S6rp expression was positively associated with Ki67 expression and histological grade (both p < 0.001), and negatively associated with ER and PgR expression (both p < 0.001). See Table 1 for IGF1R cytoplasmic expression and Additional file 1 for IGF1R membrane expression, p-mTOR and p-S6rp expression.Figure 3


Association between insulin-like growth factor-1 receptor (IGF1R) negativity and poor prognosis in a cohort of women with primary breast cancer.

Aaltonen KE, Rosendahl AH, Olsson H, Malmström P, Hartman L, Fernö M - BMC Cancer (2014)

Distribution of staining intensities for the experimental markers.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4232733&req=5

Fig3: Distribution of staining intensities for the experimental markers.
Mentions: The distribution of staining intensities for the different experimental markers is illustrated in Figure 3. For both cohorts, the association between IGF1R cytoplasm intensity and tumor characteristics can be found in Table 1. Data from IGF1R membrane staining gave comparable results and can be found in detail in Additional file 1 together with data from p-mTOR and IGF1R staining. Notable is that in Cohort I there was very strong evidence of a positive association between ER/PgR positivity and a high expression of IGF1R (p < 0.001). High p-S6rp was strongly associated with hormone receptor positivity (p < 0.001 for both ER and PgR). For p-mTOR there was very strong evidence for a positive association with Ki67 expression (p < 0.001), and slight evidence for an association with ER positivity (p = 0.068). In Cohort II, high p-mTOR expression was associated with ER positivity (p = 0.014) and higher age (p = 0.026), whereas it was negatively associated with Ki67 expression (p = 0.010). p-S6rp expression was positively associated with Ki67 expression and histological grade (both p < 0.001), and negatively associated with ER and PgR expression (both p < 0.001). See Table 1 for IGF1R cytoplasmic expression and Additional file 1 for IGF1R membrane expression, p-mTOR and p-S6rp expression.Figure 3

Bottom Line: We found that lower IGF1R expression was associated with worse prognosis for tamoxifen treated, postmenopausal women (HR = 0.70, 95% CI = 0.52 - 0.94, p = 0.016).The lack of co-activation of downstream markers (p-mTOR and p-S6rp) in the IGF1R pathway suggested that the prognostic effect was not due to complete activation of this pathway.Thus, no evidence could be found for a compensatory function of IGF1R signaling in the investigated cohorts.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE-223 81 Lund, Sweden. kristina.aaltonen@med.lu.se.

ABSTRACT

Background: Resistance towards endocrine therapy is a great concern in breast cancer treatment and may partly be explained by the activation of compensatory signaling pathways. The aim of the present study was to investigate if the insulin-like growth factor-1 receptor (IGF1R) signaling pathway was activated or deregulated in breast cancer patients and to explore if any of the markers were prognostic, with or without adjuvant tamoxifen. This signaling pathway has been suggested to cause estrogen independent cell growth and thus contribute to resistance to endocrine treatment in estrogen receptor (ER) positive breast cancer.

Methods: The protein expression of IGF1R, phosphorylated Mammalian Target of Rapamycin (p-mTOR) and phosphorylated S6 ribosomal protein (p-S6rp) were investigated by immunohistochemistry using tissue microarrays in two patient cohorts. Cohort I (N = 264) consisted of mainly postmenopausal women with stage II breast cancer treated with tamoxifen for 2 years irrespective of ER status. Cohort II (N = 206) consisted of mainly medically untreated, premenopausal patients with node-negative breast cancer. Distant disease-free survival (DDFS) at 5 years was used as end-point for survival analyses.

Results: We found that lower IGF1R expression was associated with worse prognosis for tamoxifen treated, postmenopausal women (HR = 0.70, 95% CI = 0.52 - 0.94, p = 0.016). The effect was seen mainly in ER-negative patients where the prognostic effect was retained after adjustment for other prognostic markers (adjusted HR = 0.49, 95% CI = 0.29 - 0.82, p = 0.007). Expression of IGF1R was associated with ER positivity (p < 0.001) in the same patient cohort.

Conclusions: Our results support previous studies indicating that IGF1R positivity reflects a well differentiated tumor with low metastatic capacity. An association between lack of IGF1R expression and worse prognosis was mainly seen in the ER-negative part of Cohort I. The lack of co-activation of downstream markers (p-mTOR and p-S6rp) in the IGF1R pathway suggested that the prognostic effect was not due to complete activation of this pathway. Thus, no evidence could be found for a compensatory function of IGF1R signaling in the investigated cohorts.

Show MeSH
Related in: MedlinePlus