Insulin resistance, insulin‐like growth factor I and breast cancer: A hypothesis

Kazer, Ralph R.

doi:10.1002/ijc.2910620408

Cited by 83 publications

(42 citation statements)

References 59 publications

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“…Long-term insulin therapy of patients with type 1 diabetes may explain the increased risk of endometrial cancer among diabetic women with type 1 diabetes [35]. Hyperinsulinaemia may also increase levels of bioactive oestrogens by decreasing concentrations of circulating sex hormone binding globulin [49,50]. Oestrogens have been shown to increase endometrial cancer risk by stimulating proliferation of endometrial cells [51], when unopposed by progesterone [52,53].…”

Section: Discussionmentioning

confidence: 99%

Diabetes mellitus and risk of endometrial cancer: a meta-analysis

et al. 2007

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Aims/hypothesis Diabetes has been associated with a statistically significantly increased risk of endometrial cancer in most, but not all studies. To provide a quantitative assessment of the association between diabetes and risk of endometrial cancer, we conducted a meta-analysis of casecontrol studies and cohort studies. Subjects and methods We identified studies by a literature search of PubMed and Embase through to January 2007 and by searching the reference lists of relevant articles. Summary relative risks (RRs) with 95% CIs were calculated using random-effects model. Results The analysis of diabetes (largely type 2) and endometrial cancer is based on 16 studies (three cohort and 13 case-control studies), including 96,003 participants and 7,596 cases of endometrial cancer. Twelve of the studies showed a statistically significantly increased risk and four a non-significant increased risk of endometrial cancer. In our meta-analysis we found that diabetes was statistically significantly associated with an increased risk of endometrial cancer (summary RR 2.10, 95% CI 1.75-2.53). The risk estimates were somewhat stronger among case-control (RR 2.22, 95% CI 1.80-2.74) than among cohort studies (RR 1.62, 95% CI 1.21-2.16), stronger among studies adjusting only for age (RR 2.74, 95% CI 1.87-4.00) compared with multivariate adjustment (RR 1.92, 95% CI 1.58-2.33) and slightly lower in studies performed in the USA than in those performed Europe. The analysis of type 1 diabetes and endometrial cancer was based on three studies and found a statistically significant positive association (summary RR 3.15, 95%CI 1.07-9.29). Conclusions/interpretation Results from the meta-analysis support a relationship between diabetes and increased risk of endometrial cancer.

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Section: Discussionmentioning

confidence: 99%

Diabetes mellitus and risk of endometrial cancer: a meta-analysis

et al. 2007

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“…16,17) According to this hypothesis, the previously reported positive association between estradiol concentration and breast cancer risk factors, such as obesity and fat intake, may be explained by the influence of hyperinsulinemia on serum estrogen concentrations.…”

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confidence: 96%

“…15) These observations led to the hypothesis that hyperinsulinemia or insulin resistance rather than estrogen profile may be a link between breast cancer risk factors and breast cancer. 16,17) According to this hypothesis, the previously reported positive association between estradiol concentration and breast cancer risk factors, such as obesity and fat intake, may be explained by the influence of hyperinsulinemia on serum estrogen concentrations. 18) Therefore, we evaluated the relationships between insulin resistance and potential breast cancer risk factors in postmenopausal women and examined whether insulin resistance confounds any observed relations between estrogen status and potential breast cancer risk factors.…”

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confidence: 96%

Relations of Insulin Resistance and Serum Concentrations of Estradiol and Sex Hormone‐binding Globulin to Potential Breast Cancer Risk Factors

Nagata

Shimizu

Takami

et al. 2000

Japanese Journal of Cancer Research

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There is a hypothesis that hyperinsulinemia or insulin resistance may be a mediator for breast cancer risk factors. On the other hand, some, but not all, of the well-known risk factors of breast cancer have been associated with serum estrogen concentrations. We assessed the relationships of potential breast cancer risk factors to indicators of insulin resistance, fasting plasma insulin concentration and homeostasis model assessment insulin resistance (HOMA-R), in 88 postmenopausal Japanese women. We also examined whether insulin resistance would explain the association of breast cancer risk factors with serum estradiol and sex hormone-binding globulin (SHBG). Information on potential breast cancer risk factors, such as demographic characteristics, smoking and drinking habits, diet, exercise, menstrual and reproductive factors, was obtained by self-administered health questionnaire including a validated semiquantitative food frequency questionnaire. 1) Positive association between serum estradiol and breast cancer risk has been confirmed in postmenopausal women.2, 3) The known breast cancer risk factors such as age at menarche, nulliparity, and obesity may be mediated by an estrogen mechanism. Therefore, the relationships between estrogen profile and some of the breast cancer risk factors have been investigated, but the results are inconsistent. [4][5][6][7][8] Recent epidemiological studies showed that high serum C-peptide, a peripheral marker of insulin secretion, or plasma fasting insulin level was significantly associated with risk of breast cancer.9, 10) Insulin promotes the growth of rat mammary carcinoma cells.11) Hyperinsulinemia may be a significant risk factor for breast cancer. Obesity, a well-known risk factor of postmenopausal breast cancer was accompanied by hyperinsulinemia. 12, 13) Dietary fat, a suspected breast cancer risk factor, was associated with blood insulin concentration. 13,14) Fat intake modified the binding of insulin receptors and the rate of insulin-stimulated glucose transport.15) These observations led to the hypothesis that hyperinsulinemia or insulin resistance rather than estrogen profile may be a link between breast cancer risk factors and breast cancer. 16,17) According to this hypothesis, the previously reported positive association between estradiol concentration and breast cancer risk factors, such as obesity and fat intake, may be explained by the influence of hyperinsulinemia on serum estrogen concentrations.18) Therefore, we evaluated the relationships between insulin resistance and potential breast cancer risk factors in postmenopausal women and examined whether insulin resistance confounds any observed relations between estrogen status and potential breast cancer risk factors. MATERIALS AND METHODSWe focused on women who were postmenopausal, defined as cessation of menses for 12 or more months, among the participants in the health check-up program provided by a general hospital in Gifu.19) A total of 103 postmenopausal women agreed to participate in the present study a...

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“…thyroid hormones; Stewart et al, 1990) and growth factors [i.e. insulin-like growth factor (IGF-I); Kazer, 1995].In post-menopausal women, the involvement of oestrogens is suggested by the association of breast cancer with several hormone-related characteristics (e.g. age at menopause, parity, being overweight, etc.)…”

mentioning

confidence: 99%

“…thyroid hormones; Stewart et al, 1990) and growth factors [i.e. insulin-like growth factor (IGF-I); Kazer, 1995].…”

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confidence: 99%

Selected medical conditions and risk of breast cancer

Talamini

Franceschi²,

Favero³

et al. 1997

Br J Cancer

133

102

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Summary Several diseases are known or suspected to be associated with altered levels of hormones and growth factors that may influence breast cancer risk. To elucidate this possibility, we studied the relationship between 23 medical conditions or procedures and breast cancer risk by means of data from a multicentric case-control study conducted between 1991 and 1994 in six Italian areas. The study included 2569 histologically confirmed incident cases of breast cancer (median age 55 years, range 23-74 years) and 2588 control women (median age 56 years, range 20-74 years) admitted to the same hospitals as cases for a variety of acute conditions unrelated to known or suspected risk factors for breast cancer. After allowance for education, parity and body mass index, elevated odds ratios (ORs) emerged for history of diabetes mellitus in post-menopausal women (OR = 1.5, 95% Cl 1.1-2.0), hypertension in pregnancy (OR = 1.8, 95% Cl 1.0-3.4) and breast nodules (OR = 1.3, 95% Cl 1.0-1.7). Risk decreases were associated with ovarian ablation for ovarian cysts (OR = 0.5, 95% Cl 0.3-0.7) and with thyroid nodules (OR = 0.7, 95% Cl 0.5-0.9) but not with the combination of any type of benign thyroid disease. While most examined conditions seemed unrelated to breast cancer risk, the association with late-onset diabetes is of special interest as it suggests a role of hyperinsulinaemia and insulin resistance in breast cancer promotion. It also points to preventive lifestyle modifications.Keywords: breast cancer; diabetes; hypertension; benign breast disease; benign thyroid disease; ovarian cysts It has been hypothesized that breast cancer risk is determined by cell proliferation in response to sex hormones (Henderson et al, 1988) and possibly other hormones (e.g. thyroid hormones; Stewart et al, 1990) and growth factors [i.e. insulin-like growth factor (IGF-I); Kazer, 1995].In post-menopausal women, the involvement of oestrogens is suggested by the association of breast cancer with several hormone-related characteristics (e.g. age at menopause, parity, being overweight, etc.) (Franceschi et al, 1996a;Talamini et al, 1996). Several investigators found that post-menopausal women who subsequently developed breast cancer tended to show higher levels of oestrone, total and free oestradiol and a lower per cent of oestradiol bound to sex-hormone binding globulin (SHBG) than women who remained free of cancer (Toniolo et al, 1995;Lipworth et al, 1996). SHBG concentration determines oestrogen bioavailability and is influenced by several physiological and pathological conditions. Obesity, for instance, increases peripheral aromatization of androgens but also reduces SHBG concentration (Enriori and Reforzo-Membrives, 1984). Insulin and IGF-I are powerful negative regulators of SHBG synthesis in vitro and may stimulate breast cancer proliferation in several ways (Macaulay, 1992). In the presence of functioning ovaries (i.e. premenopausal women), the peripheral aromatization of androgens is relatively unimportant and the association between fe...

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Insulin resistance, insulin‐like growth factor I and breast cancer: A hypothesis

Cited by 83 publications

References 59 publications

Diabetes mellitus and risk of endometrial cancer: a meta-analysis

Diabetes mellitus and risk of endometrial cancer: a meta-analysis

Relations of Insulin Resistance and Serum Concentrations of Estradiol and Sex Hormone‐binding Globulin to Potential Breast Cancer Risk Factors

Selected medical conditions and risk of breast cancer

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