Compensatory role of insulin-like growth factor 1 receptor in estrogen receptor signaling pathway and possible therapeutic target for hormone therapy-resistant breast cancer

Iida, Masafumi; Tsuboi, Kouki; Niwa, Toshimitsu; Ishida, Toru; Hayashi, Shin Ichi

doi:10.1007/s12282-018-0922-0

Cited by 30 publications

(24 citation statements)

References 29 publications

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“…These processes turn into clinically overt relapses after some years [43]. This is in line with other research, which has found a positive correlation between tumor size and relapse [44], and also between tumor size and development of have given such CTCs a systemic biological support from a triple survival benefit through the Warburg effect [12], the insulin /IGF-1 axis [51] and the paracrine signaling with distant located adipocytes [11]. Furthermore, increased IR/IGF signaling promotes the protein synthesis in the same way the PRpathway does.…”

Section: Discussionsupporting

confidence: 87%

“…Metformin attenuates the systemic biological effect of IR /IGF on tumor promoting signaling by improving insulin sensitivity and suppressing liver glucose output, which leads to reduced levels of systemic circulating insulin [14]. This will further mitigate paracrine signaling, overcome endocrine resistance [51,56] and improve prognosis in breast cancer [57][58][59][60]. The present study supports the hypothesis that adjuvant metformin or other insulinlowering therapeutic interactions may have their largest effect in breast cancer patients with ERpositive T2 tumors.…”

Section: Discussionsupporting

confidence: 82%

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Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

Lende

Austdal

Varhaugvik

et al. 2019

Preprint

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Background The influence of carbohydrates in breast cancer is conflicting. Objective To determine whether preoperative per-oral carbohydrate load influences proliferation in breast tumors. Design Randomized controlled trial. Setting University hospital with primary and secondary care functions in South-West Norway. Patients A population-based cohort of 61 patients with operable breast cancer. Intervention Per-oral carbohydrate load (preOp™) 18 and 2-4 hours before surgery (n=26) or standard pre-operative fasting procedure with free consume of tap water (n=35). Measurements Primary outcome was post-operative tumor proliferation measured as mitotic activity index (MAI). Secondary outcomes were changes in serum insulin, insulin-c-peptide, glucose, IGF-1 and IGFBP3. Other secondary outcomes were patients´ well-being and clinical outcome (median follow-up 88, range 33-97 months). Results In the estrogen receptor (ER) positive subgroup (n=50), high proliferation (MAI≥ 10) occurred more often in the carbohydrate group (CH) than in the fasting group (p=0.038). Progesterone receptor (PR) was more frequently negative in the CH-group (p=0.014). CH-patients had a significant between group rise in insulin (+ 24.31 mIE/L, 95% CI, 15.34 mIE/L to 33.27 mIE/L), insulin c-peptide (+ 1.39 nM, 95% CI, 1.03 nM to 1.77 nM), but reduced IGFBP3 levels (– 0.26 nM; 95% CI, – 0.46 nM to – 0.051 nM). CH-Intervention ER-positive patients had poorer relapse free survival (73%) than the fasting group (100%) (p=0.012; HR= 9.3 (95%CI, 1.1 to 77.7)). In the ER-positive patients, only tumor size (p=0.021; HR=6.07, 95%CI=1.31 to 28.03) and CH-or-fasting grouping (p=0.040; HR=9.30, 95% CI=1.11 to 77.82) had independent prognostic value. The adverse clinical outcome of carbohydrate loading occurred only in T2 patients with Relapse Free Survival of 100% in the fasting group vs. 33% in the CH-group (p=0.015; HR= inf). The CH-group reported less pain on day 5 and 6 compared to the control group (p<0.001) but showed otherwise no factors related to well-being. Limitation Only applicable to ER-positive breast cancer patients with T2-tumors. Conclusions Preoperative carbohydrate load increases proliferation and PR-negativity in ER-positive patients and worsens clinical outcome in ER-positive T2-patients. Keywords: breast cancer, carbohydrate load, proliferation, insulin, insulin c-peptide, IGF-1, IGFBP3, tumor size, relapse free survival, breast cancer specific survival

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 82%

Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

Lende

Austdal

Varhaugvik

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Metformin attenuates the systemic biological effect of IR /IGF on tumor promoting signaling by improving insulin sensitivity and suppressing liver glucose output, which leads to reduced levels of systemic circulating insulin [14]. This will further mitigate paracrine signaling, overcome endocrine resistance [51,57] and improve prognosis in breast cancer [58][59][60][61]. The present study supports the hypothesis that adjuvant metformin or other insulinlowering therapeutic interactions may have their largest effect in breast cancer patients with ERpositive T2 tumors.…”

Section: Discussionsupporting

confidence: 82%

“…The amount of liberated circulating tumor cells (CTCs) from the primary tumor is known to sharply increase during surgery [50]. Thus, the administered carbohydrates may have given such CTCs a systemic biological support from a triple survival benefit through the Warburg effect [12], the insulin /IGF-1 axis [51] and the paracrine signaling with distant located adipocytes [11]. Furthermore, increased IR/IGF signaling promotes the protein synthesis in the same way the PRpathway does.…”

Section: Discussionmentioning

confidence: 99%

Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

Lende

Austdal

Varhaugvik

et al. 2019

Preprint

View full text Add to dashboard Cite

Background The influence of carbohydrates in breast cancer is conflicting.Objective To determine whether preoperative per-oral carbohydrate load influences proliferation in breast tumors.Design Randomized controlled trial.Setting University hospital with primary and secondary care functions in South-West Norway.Patients A population-based cohort of 61 patients with operable breast cancer.Intervention Per-oral carbohydrate load (preOp™) 18 and 2-4 hours before surgery (n=26) or standard pre-operative fasting procedure with free consume of tap water (n=35).Measurements Primary outcome was post-operative tumor proliferation measured as mitotic activity index (MAI). Secondary outcomes were changes in serum insulin, insulin-c-peptide, glucose, IGF-1 and IGFBP3. Other secondary outcomes were patients´ well-being and clinical outcome (median follow-up 88, range 33-97 months).Results In the estrogen receptor (ER) positive subgroup (n=50), high proliferation (MAI≥ 10) occurred more often in the carbohydrate group (CH) than in the fasting group (p=0.038). Progesterone receptor (PR) was more frequently negative in the CH-group (p=0.014). CH-patients had a significant between group rise in insulin (+ 24.31 mIE/L, 95% CI, 15.34 mIE/L to 33.27 mIE/L), insulin c-peptide (+ 1.39 nM, 95% CI, 1.03 nM to 1.77 nM), but reduced IGFBP3 levels (– 0.26 nM; 95% CI, – 0.46 nM to – 0.051 nM). CH-Intervention ER-positive patients had poorer relapse free survival (73%) than the fasting group (100%) (p=0.012; HR= 9.3 (95%CI, 1.1 to 77.7)). In the ER-positive patients, only tumor size (p=0.021; HR=6.07, 95%CI=1.31 to 28.03) and CH-or-fasting grouping (p=0.040; HR=9.30, 95% CI=1.11 to 77.82) had independent prognostic value. The adverse clinical outcome of carbohydrate loading occurred only in T2 patients with Relapse Free Survival of 100% in the fasting group vs. 33% in the CH-group (p=0.015; HR= inf). The CH-group reported less pain on day 5 and 6 compared to the control group (p<0.001) but showed otherwise no factors related to well-being.Limitation Only applicable to ER-positive breast cancer patients with T2-tumors.Conclusions Preoperative carbohydrate load increases proliferation and PR-negativity in ER-positive patients and worsens clinical outcome in ER-positive T2-patients.

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“…Dibaba hyperinsulinemia is an independent risk factor of BC. Furthermore, blocking the IGF pathway may be an effective method for cases of hormone therapy-resistant BC (26)(27)(28). In Her2-positive patients with BC who received neo-chemotherapy, the low level of IGF-1 was significantly associated with higher pCR rate but not with recurrence and mortality (29).…”

Section: Discussionmentioning

confidence: 99%

The prognostic link between metabolic syndrome and the different breast cancer molecular subtypes: a case control study.

Chen¹,

Zhang²,

Chen³

et al. 2020

Preprint

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Background Metabolic syndrome (MetS) is an important factor related to the poor prognosis of breast cancer (BC). Molecular heterogeneity in the tumor may affect the consequence of BC. The main purpose of this study was to assess the prognostic link between MetS and the different BC molecular subtypes. Methods A total of 960 patients with BC were recruited from January 2010 to June 2014. The relationship between MetS and disease prognosis was assessed by using univariate and multivariate analyses. Results At recruitment, MetS was diagnosed in 199 patients (20.7%). The mean follow-up period was 68.5 months (range, 2–103 months). MetS remained significantly associated with 64% increased risk of recurrence (Hazard Ratio (HR)=1.64; 95% confidence interval (CI) 1.19–2.27, P<0.01) and twofold increased risk of mortality (HR=2.02, 95% CI 1.29–3.16, P<0.01) according to multivariate analysis. By reviewing BC molecular subtypes, the significant associations remained in the subsets of Luminal A (HR=3.1, 95% CI 1.28–4.57, P=0.01), Luminal B (Her2-negative) (HR=3.3, 95% CI 1.31–8.33, P=0.01), and Her-2-positive (non-Luminal) (HR=2.2, 95% CI 1.10–4.39, P=0.03). Conclusions MetS was significantly related to unfavorable prognosis in operable BC, especially in the subgroup of Luminal A. More studies are needed to definitively determine which factors influence the association of MetS with Luminal A subtype.

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Compensatory role of insulin-like growth factor 1 receptor in estrogen receptor signaling pathway and possible therapeutic target for hormone therapy-resistant breast cancer

Cited by 30 publications

References 29 publications

Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

The prognostic link between metabolic syndrome and the different breast cancer molecular subtypes: a case control study.

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