Breast Cancer Risk Factors in Overweight Obese Women
Background: Obesity and breast cancer are both chronic diseases with related risk factors. Obesity and waist to hip ratio were demonstrated as predictors of breast cancer while altered lipid profiles and high oestrogen levels were associated with carcinogenesis of the breast with poorly understood mechanisms. This study aims at evaluating these risk factors in breast cancer in overweight and obese women to enable early diagnosis and disease prevention. Method: This study is mostly laboratory based. 99women aged 22-82 years were recruited after informed consent. 38, 29, 32 were overweight/obese (OO), breast cancer (BC) and apparently healthy women (controls) respectively. Height and weight were measured and body mass Index (BMI) was calculated. Waist and Hip circumference were measured and ratio (W/H) obtained. 10 mls of blood was obtained from each subject for the determination of Oestradiol(E) by ELISA(Adaltis, Italia), total cholesterol(C), triglycerides(TG), and high density lipoprotein cholesterol(HDL-C) by enzymatic method(DIALAB). Low density lipoprotein cholesterol l(LDL-C) was calculated. The data was analysed statistically using SPSS version 11.0 to find relationships/associations. Results: BMI, C and LDL.C - breast cancer and cardiovascular risk factors were significantly higher both in overweight/obese and breast cancer subjects compared with controls (p<0.05). Breast cancer subjects had significantly higher levels of W/R, TG and parity compared with controls and overweight/obese groups(p<0.05). Only E2 was significantly higher in breast cancer than controls in post menopausal women(p=0.01) while only TG was significantly higher in breast cancer compared with controls(p<0.004) in pre-menopausal women.
Conclusion: Results suggest that C and LDL-C present in OO group may not relate to E, a known risk factor in breast cancer, but together with BMI and W/H ratio may have implication in the development of coronary artery disease (CAD).
Key words: Obesity, overweight, breast cancer, lipids, hormones
Obesity is said to be a neglected disease. It is frequently thought of as a self-inflicted condition than a disease, which can be prevented and cured by self control and determination (Bjorntorp, 1997). It is defined as body mass index (BMI) above 30kg/m2, while overweight is regarded as a BMI between 25 and 29.9kg/m2 (WHO, 1998). It is a significant public health crisis in the developed world and its prevalence is also rising rapidly in numerous developing countries (Uwaifo and Arioglu, 2004).
Obesity is associated with a number of potential chronic diseases such as breast cancer and potentiates significantly the morbidity and mortality associated with these diseases. While a cause and effect relationship has not been exhaustively demonstrated, amelioration of these diseases with significant weight loss suggests that the obesity factor plays an important role in their development (Christian and James, 2005; Uwaifo and Arioglu, 2004; Mctiernan, 2003).
Breast cancer, which is defined as malignant tumour of the breast (Elizabeth and Martin, 2005) is the most frequently diagnosed malignancy. It is the second commonest cause of cancer death amongst women in industrialized countries(Greenlee et. al., 2000). Cancer studies in Nigeria showed that at the creation of the first cancer registry in 1960 in Ibadan, cancer of the cervix was the most frequently observed cancer. Breast cancer later (1980-1996) emerged as the commonest malignancy in women with 25% increase and 23.1% increase for cancer of the cervix (Adebamowo and Adekunle, 1999; Olufemi, 2000; Mandong et. al., 2004).
The aetiology of breast cancer is still not well understood (Mazhar and Waxman, 2006; Issam et. al. 2006; Olufunmilayo, 2000). However, obesity including abdominal obesity and adult weight gain has been highlighted in several studies as risk factor for breast carcinogenesis ( Brinton & Swanson, 1992; Hunter & Willet, 1993; Ballard-Barabash, 1994, Sonneschein et. al., 1999; Adebamowo et. al., 2003). Other risk factors include high exposure to endogenous and exogenous hormones including oestradiol (Bernstein & Ross, 1993, Hulka & Stark, 1995; The endogenous hormone group, 2002), aberrant expression of lipids and lipoproteins in serum (Farid et. al., 2003; Han & colleagues 2005; Anne-Sofie et. al. 2003), age (Hulka & Stark, 1995; Issam et. al., 2006) including age at menarche, at menopause and at first birth, family history of breast cancer (Marie-Claire et, al., 1993; Hulka, 1996), diet and physical inactivity (Inger et. al., 1997; McTiernan, 2003), and being a female (Issam et. al., 2006).
The mechanism for the association between obesity and breast cancer risk is not established, (Judd et. al., 1982; McTiernan, 2003). Both disorders are chronic with related risk factors and present enormous burden to society by increasing medical cost and human suffering. It was observed that the situation is likely to degenerate in the near future unless measures are taken such as lifestyle modification and other potential mechanisms with beneficial effects, (Ames, 1983; Hoffman et. al., 1996).
Farid et. al. (2003), Han & Colleagues (2005) and Anne-Sofie et. al (2005) demonstrated that unfavourable lipid profile and high oestrogen levels in serum were associated with carcinogenesis of the breast.
Cross - cultural studies have suggested that the high incidence of breast cancer in developed countries may be linked to the high prevalence of overweight and obesity and to a high energy intake (Stoll, 2000; Mctiernan, 2003; Darling, 2002). Shifts in diet and activity are consistent with these changes although there is paucity of information in understanding all contributory factors (Popkin and Doak, 1998). Obesity in many developing countries is increasing rapidly (Uwaifo and Arioglu, 2004) and the lifestyles of Nigerians are changing in favour of lifestyles of western developed countries.
Obesity was observed as risk factor for breast cancer in postmenopausal women but protective in premenopausal women. Recently W/H ratio was reported as a predictor of pre and postmenopausal breast cancer (Sonneschein et. al., 1999; Adebamowo et. al., 2003). This study aims at identifying potential risk factors of breast cancer and their involvement in the possible development of breast cancer in overweight/obese women to assist in early diagnosis and prevention.
MATERIALS AND METHODS
A total of 99 female subjects, 38 overweight/obese, 29 breast cancer patients and 32 controls were recruited for the study after informed consent. The age ranges for the overweight/obese breast cancer and control subjects were 20-70, 20-85, 20-70 years respectively.Overweight/obese subjects were apparently healthy women (21 obese and 17 overweight) selected randomly in Ibadan. Breast cancer patients were recruited from the surgical oncology unit of the Lagos University Teaching Hospital (LUTH), Idi-Araba and Lagos State University teaching Hospital (LASUTH), Ikeja. They were newly diagnosed and were not on any treatment. Control subjects were apparently healthy women having BMI between 18.5 and 24.9 (WHO, 1998). They were selected from staff of the University College hospital (UCH), Ibadan, University of Ibadan, LUTH and LASUTH.
The blood pressure of all was measured to exclude those with hypertension. A semi-structured pretest questionnaire with details of demographic data- reproductive, diet, activity and health history was also administered on all subjects. Premenopausal patients were recruited at the mid-luteal phase of the menstrual cycle. Subjects were considered menopausal after reporting if they had not menstruated in at least 6 months (Elizabeth et, al. 2001). Those suffering from diabetes and other chronic diseases including those on hormonal medications and lipid lowering drugs were exempted.
Anthropometric indices such as height and weight were measured and body mass index (BMI) calculated as weight (kg)/ Height2 (m2) while waist and hip circumferences were measured and Waist to hip ratio calculated as waist circumference/ hip circumference.
COLLECTION OF BLOOD
After an overnight fast by the subjects, 10ml of venous blood sample was aseptically obtained from the antecubital fossa vein using new disposable pyrogen free needles and syringes. 5ml of the blood was put in EDTA tubes and were centrifuged in a Universal 32 centrifuge machine (Heltich, Zentrifugen, Germany) at 500g for 10 minutes. The plasma obtained was stored at -200C for lipid profile (total cholesterol, triglycerides (TG) and high density lipoprotein cholesterol (HDL-C)) determination. The remaining 5ml of blood were dispensed in non-additive serum tubes, which were kept for 1-2 hours on the desk after which they were centrifuged as stated above. The serum separated was stored at -200C for the determination of estradiol (E2).
ANALYSIS OF BIOCHEMICAL INDICES
Oestradiol (E2) was determined by solid phase enzyme immunoassay method using commercially kits (Adaltis Italia S.P. A). Triglyceride, total cholesterol, high density lipoprotein cholesterol cholesterol were determined by enzymatic assay using Dialab kit, Austria . Low density lipoprotein cholesterol levels were obtained from the formula developed by Friedwald et. al. (1972).
Table1 shows the comparison of breast cancer risk factors-AM1, parity,BMI,WHR,TG,T.chol.,LDL.C, HDL.C in Overweight/obese, breast cancer and control subjects. Differences in all indices except AM1 and HDL. C were significant (p<0.05). BMI was significantly higher in breast cancer and overweight/obese groups than controls(p=0.000). The difference in BMI between breast cancer and overweight/obese groups was insignificant(p<0.05). Significantly higher differences were observed in WHR in breast cancer compared with controls and overweight/obese(p<0.05). Overweight/obese had higher WHR than controls but this not statistically significant(p<0.057). Comparisions of parity showed significantly higher differences in breast cancer group compared with both con trols and overweight/obese groups. The difference between overweight/obese and control subjects were insignificant(p=0.137). Breast cancer subjects had significantly higher levels of TG compared with controls and overweight/obese groups(p<0.03). No significant difference was observed between overweight/obese and controls(p=0.881). For both T.chol. and LDL.C, Breast cancer and overweight and obese groups had significantly higher levels than controls(p<0.038). The differences between overweight/obese and breast cancer groups were insignificant(p>0.880).
Table 2 shows comparison of all breast cancer risk factors between overweight and obese groups which did not show any statistically significant differences (p<0.05).
Table 3 shows comparison of mean breast cancer risk factors AM1,AM2, parity,BMI,WHR,TG,T.chol.,LDL.C, HDL.C - in post menopausal controls, overweight/obese and breast cancer subjects. Only BMI,WHR and E2 were significantly different (p<0.05).WHR was significantly higher in breast cancer groups compared with overweight/obese and control groups(p=0.015).The difference between overweight /obese groups and controls was not significant(p=0.6).E2 was significantly higher in only in breast cancer than controls(p=0.01).
Table 4 shows the comparison of breast cancer risk factors-AM1, parity, BMI, WHR, TG, T.chol., LDL.C, HDL.C in premenopausal overweight/obese, breast cancer and control subjects. AMI, parity, BMI and WHR were significant (p<0.05). BMI was significantly higher in overweight/obese groups compared with controls and breast cancer groups as well as breast cancer compared with controls(p<0.006). On the other hand,WHR was higher in breast cancer compared with controls and overweight/obese groups. The difference between overweight /obese and controls was not significant(p=0.06). Parity was significantly higher in breast cancer than controls and overweight /obese subjects as well as overweight/obese compared with controls(p<0.017). Only TG was significantly different between groups amongst the biochemical parameters tested. TG was significantly higher only in breast cancer compared with controls(p<0.004).
Table 5 shows comparison of mean breast cancer risk factors in pre and post menopausal controls. There were significant differences in parity, TG and oestradiol(p<0.05).
Table 6 shows comparison of mean breast cancer risk factors in pre and post menopausal overweight/obese subjects. There were significant differences in parity, oestradiol but not TG(p<0.05).
Table 7 shows comparison of mean breast cancer risk factors in pre and post menopausal breast cancer subjects. Only E2 was significantly different (p<0.05).
Table 8 shows correlations between breast cancer risk factors in controls, obese/overweight and breast cancer groups. Significant differences were observed in correlations of age with TG and E2, T.Chol. with HDL.C and LDL.C. in all groups tested(p<0.05).Only correlations between age and E2 was negative. Parity correlated significantly positively with AM2 and TG in both control and overweight/obese groups but not breast cancer group(p<0.05). Age correlated significantly and positively with parity while TG correlated negatively and significantly with LDL.C in overweight/obese and breast cancer groups but not controls(p<0.05).
BMI correlated positively and significantly with parity in control group only(p<0.05). Age correlated significantly with AM2, parity with LDL.C while BMI correlated with WHR in overweight/obese group only. These correlations were positive. WHR correlated significantly and positively with parity and but negatively with E2 in breast cancer group only(p<0.05).
Obesity is a significant public health crisis in the developed world with rapidly rising prevalence in numerous developing countries (Uwaifo and Ariolu, 2004) Obesity including abdominal obesity and adult weight gain has been highlighted in several studies as risk factor for breast carcinogenesis ( Brinton & Swanson, 1992; Hunter & Willet, 1993; Ballard-Barabash, 1994, Sonneschein et. al., 1999; Adebamowo et. al., 2003)
.In this present study, BMI was significantly elevated in both breast cancer and overweight/obese groups irrespective of reproductive stage(Tables1,3,4). Our observations are contrary to reports that showed obesity is an independent risk factor in postmenopausal breast cancer (Sonneschein et. al. 1999; Adebamowo et al., 2003). WHR which is also independent of reproductive stage appears to be a more relevant as a breast cancer risk factor as it is significantly higher in breast cancer subjects than controls(p<0.05)(Tables 1,3,4). Abnormal WHR has been shown to be a predictor of breast cancer risk in both premenopausal and postmenopausal women(Sonneschein et. al., 1999; Adebamowo et. al., 2003) and may be due to aberrant insulin signaling leading to increased endogenous androgen and oestrogen levels (McPherson et. al. 2000). It appears in this present study that BMI may not be an important predictor of breast cancer if it correlates with WHR in overweight/obese women(Table 8) contrary to reports by others((Sonneschein et. al., 1999; Adebamowo et. al., 2003) who reported that in premenopausal women, obesity was protective against breast cancer among women with a low (<0.85) waist-hip-ratio (WHR)- a parameter for abdominal fat deposition. Puepet et al.(2002) observed that most overweight and all obese Nigerian subjects had abnormal WHR (>0.85). However, positive correlations of WHR with parity may be critical to the development of breast cancer(Table 8). Parity in this study, was significantly elevated in both breast cancer and overweight/obese groups only in premenopausal breast cancer(p<0.05).
Han & Colleagues (2005), Farid et al. (2005) and Anne-Sofie et al. (2005) demonstrated that unfavourable lipids and high oestrogen levels in serum were associated with the carcinogenesis of the breast. In this present study, breast cancer and overweight/obese groups had significantly higher levels of T.chol. and LDL.C than controls(p<0.038)(Table 1). TG and E2 are both dependent on reproductive stage(Table 2).TG appears to be a more specific predictor of premenopausal breast cancer while E2 appears to be a more specific postmenopausal breast cancer. Similar to this present study, the levels of oestrogen have been shown to increase in postmenopausal obese women because adipose tissue (fat stores) is the main site of oestrogen production through aromatization of androgens at menopause (Krotkiewski et al. 1983; Siiteri, 1987). The risk of developing breast cancer might be positively related with the overall exposure to ovarian hormones (Hulka, 1996; The endogenous hormone group, 2002). Oestrogen is required for normal tissue growth and development, but is also responsible for the promotion of certain tumours especially breast cancer (Miller, 2004). 30-50% of breast cancers are considered oestrogen-dependent (Henderson et. al., 1982; Sedlaak et. al., 1984), and regression can be achieved by reducing blood and tissue levels of oestrogens.
Different mechanisms have been postulated for breast cancer development. Firstly, triglycerides tend to displace oestradiol from its tight binding to sex hormone-binding globulin which are known to be in low levels in obese women(Inger et. al.,1997; Elizabeth, 2001). Secondly, the relationship between obesity and breast cancer risk (Judd et. al., 1982) may be attributed, at least in part, to an increase in the serum concentration of bioavailable oestradiol resulting from increased production of oestrogens by aromatase in the adipose tissue (Krotkiewski et al, 1983; Siiteri 1987; Ackerman et. al., 1981) and decrease in the serum concentration of sex hormone binding globulin (Judd et. al., 1982).
We also observed differences in specific indices in comparison between between reproductive stages (pre and post menopausal women) within groups. Significant differences were observed in parity, TG and oestradiol in controls; parity and oestradiol but not TG in overweight/obese women; E2 only in the breast cancer groups(p<0.05). These findings may be significant the the management of overweight /obese and breast cancer subjects.
In the face of the observations made in this study, measures such as lifestyle modification and other potential mechanisms with beneficial effects (Amos, 1983; Hoffman et. al., 1996) should be taken, to avoid the increase of both cardiovascular diseases and breast cancer in the near future. This will reduce the financial burden of taking care of these diseases on the individual, society and government. A large well controlled study is needed to identify specific indices that could predict breast cancer.
Results in this present study suggest that BMI, Tchol. and LDL.C and parity are common to both breast cancer and overweight/obese groups. They could be early markers of breast but might have implications as cardiovascular risk factors. WHR, TG and E2 appear to be specific markers in breast cancer. E2, TG and parity appear reproductive stage dependent. TG appear to be premenopausal breast cancer marker while E2 appears to be post menopausal breast cancer marker. . Significant differences were observed in parity, TG and oestradiol in controls; parity and oestradiol but not TG in overweight/obese women; E2 only in the breast cancer groups(p<0.05). We believe that these findings improve the current the the management of overweight /obese and breast cancer subjects.
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