Metabolic Health, Insulin, and Breast Cancer: Why Oncologists Should Care About Insulin

Abstract

The potential association between obesity and TNBC has been a subject of intense research study. As outlined below, studies investigating the potential relationship between obesity and TNBC have been inconsistent. This is a summary of some of the key studies that have been recently published.The Carolina Breast Cancer Study is a North Carolina population-based case-controlled study of breast cancer, conducted in three phases (28). The current study phase, Phase 3 (years 2008-2014), includes women resident in 44 North Carolina Counties (28), employing randomized recruitment to oversample African-American/Black women and women under age 50 (28). Waist to hip ratio (WHR) was compared between the highest (≥0.84) and lowest (<0.77) groups vs. the basal-type subset of TNBC. There was an increased risk [odds ratio (OR) = 2.3; 95% CI, 1.4-3.6] for basal-type TNBC in women with higher WHR (43). Premenopausal women (OR = 1.8; 95% CI, 1.0-3.4) and post-menopausal women (OR = 2.7; 95% CI, 1.3-5.4) with the highest WHR had increased risk of developing basal-type TNBC compared to the lowest WHR (43). Basal-type breast cancer was observed to be highest among premenopausal African-American/Black women (43). There was no significant association between increased BMI (defined as BMI ≥ 25 kg/m 2 ) and basal-type TNBC.The Appalachian Study investigated the potential association between obesity (defined as BMI ≥ 30 kg/m 2 ) and TNBC in 620 predominantly non-Hispanic White women in rural Appalachia. This study reported a significant association between obesity and the incidence of TNBC (29).Women's CARE study is a case-controlled study of BMI and breast cancer risk in non-Hispanic White women and African-American/Black women. The Women's CARE study reported (1) an inverse association between a woman's BMI at age 18 and premenopausal ER-/PR-breast cancer and (2) a positive association between current BMI and post-menopausal ER+/PR+ breast cancer (30).

Insulin/IGF Axis in Breast Cancer: Clinical Evidence and Translational Insights

“…Moreover, women with triple-negative tumors seem to have a high prevalence of metabolic syndrome, characterized by increased BMI and circulating levels of insulin and related growth factors, leading to uncontrolled cell proliferation [ 44 ] and worse prognosis. Several other studies were conducted to investigate the potential role of obesity in TNBC development, with controversial results [ 45 ].…”

Microenvironmental Determinants of Breast Cancer Metastasis: Focus on the Crucial Interplay Between Estrogen and Insulin/Insulin-Like Growth Factor Signaling

“…However, IR-A is intimately linked to the mitogenic MAPK/mammalian target of rapamycin (mTOR) cascade rather than to the PI3K/Akt metabolic cascade also in response to insulin ( Frasca et al, 1999 ). As a consequence, BC cells do not share the insulin resistance of peripheral tissues of obese patients ( Yee et al, 2020 ). Therefore, IR-A overexpression can be seen as a way BC cells exploit to overcome insulin resistance of obese patients and allow full response to the estrogen/IIGFs cross-talk ( Belfiore et al, 2017 ).…”

Integrated analysis of Solute carrier family-2 members reveals SLC2A4 as an independent favorable prognostic biomarker for breast cancer

“…When exposed to hyperinsulinemia, cancer cells gain a selective growth advantage compared to normal tissues [ 46 ]. It has been found that the higher breast cancer incidence and higher all-cause mortality after breast cancer were significantly correlated with higher levels of insulin resistance in postmenopausal women [ 49 , 50 ]. Analyzing protein–protein interaction network in STRING database, SLC2A4 also participates in the translocation of SLC2A4 ( GLUT4 ) to the plasma membrane and protein localization to plasma membrane through enriched proteins such as EXOC5 and C2CD5 , which play an important role in human cancers.…”