breast cancer , the most common cancer in women worldwide , accounted for 1.7 million new cases in 2012 , comprising a quarter of all new cancer cases . while traditional risk factors for breast cancer include age , family history of cancer , and reproductive and menstrual history , the national cancer institute also recognizes overweight , lack of physical activity , and consumption of alcohol as risk factors .
metabolic syndrome ( ms ) is a cluster of pathophysiological disorders comprising central obesity , insulin resistance , high blood pressure , and dyslipidemia .
reaven 's definition of ms in 1988   was followed by definitions from the world health organization , national cholesterol education program 's adult treatment panel iii ( ncep atp iii ) , american heart association / national heart , lung , and blood institute , and the international diabetes federation .
these criteria include the presence of three or more of the following : abdominal obesity ( waist circumference  35 inches in women ) , triglycerides  150  mg / dl , high density lipoprotein cholesterol ( hdl - c ) < 50  mg / dl , blood pressure ( bp )  130/85  mmhg , and fasting glucose  110  mg / dl .
ms is estimated to be prevalent in at least a quarter of the adults in the americas , in europe , and in india .
ms has been identified as a risk factor for several cancers , particularly breast , pancreatic , colorectal , and prostate cancers [ 1015 ] .
individual components of ms , for example , abdominal obesity , high blood glucose , high bp , high triglycerides , and low hdl , are positively associated with the development of certain cancers , most notably breast cancer [ 1627 ] .
while studies show a positive association of breast cancer with diabetes [ 19 , 2833 ] and obesity [ 16 , 34 , 35 ] , others show a negative association with obesity in premenopausal women [ 3638 ] .
mixed results also characterize hypertension [ 22 , 23 , 39 , 40 ] and dyslipidemia [ 22 , 41 , 42 ] as risk factors for breast cancer .
in addition , although individual components of ms may not be strongly associated with the development of breast cancer , their combination may elevate the risk [ 13 , 14 , 4356 ] .
for example , ms may activate different molecular pathways through endocrine , metabolic , and immune cell changes , which in turn influence breast tumorigenesis .
such pathways that enhance breast cancer cell proliferation and inhibit apoptosis include ( 1 ) increased levels of circulating estrogen , for example , estradiol [ 52 , 54 , 57 ] , ( 2 ) higher levels of insulin [ 58 , 59 ] , ( 3 ) decreased level of circulating adiponectin , ( 4 ) increased plasma leptin concentration , and ( 5 ) increased production of proinflammatory cytokines , such as interleukin-6 and tumor necrosis factor alpha .
previous epidemiologic studies on ms and breast cancer risk show contrary results . for example , only four [ 13 , 14 , 43 , 51 ] of eight studies [ 13 , 14 , 43 , 48 , 51 , 6264 ] reported a statistically significant association between ms and risk of breast cancer .
this might invite a conclusion that the association between ms and breast cancer risk is unknown .
however , such an inference would be based on the vote - counting approach , an approach that ignores the magnitude of the association . a recent systematic review and
meta - analysis of ms and postmenopausal breast cancer found that ms was moderately associated with the risk of postmenopausal breast cancer .
however , to the best of our knowledge , no meta - analytic research has addressed the conflicting results from individual studies of ms and breast cancer risk in all adult women .
therefore , the purpose of this study was to use the aggregate data meta - analytic approach to examine the association between ms and breast cancer risk in women .
the a priori inclusion criteria for this study were as follows : ( 1 ) observational studies using cohort ( both prospective and retrospective ) , case - control , or nested case - control study designs ; ( 2 ) studies examining the association between ms ( presence of a cluster of three or more metabolic abnormalities ) and breast cancer incidence , as defined by the authors ; ( 3 ) studies with adult females  18 years of age as participants ; ( 4 ) english - language studies published as journal articles , doctoral dissertations , or masters ' theses ; ( 5 ) published and indexed studies up to june 30 , 2012 ; and ( 6 ) studies reporting sufficient data ( e.g. , rate ratios , risk ratios , odds ratios , standardized incidence ratios , hazard ratios , or frequencies ) for calculating a common effect size .
neither lobular carcinoma in situ nor ductal carcinoma in situ breast cancer cases were excluded from the study .
studies not meeting all inclusion criteria were excluded from this review . excluded studies were those that ( 1 ) were not published as full reports , such as conference abstracts and letters to the editors ; ( 2 ) only examined individual components of ms ; ( 3 ) measured the ms variables at time of cancer diagnosis ; ( 4 ) used cancer mortality , rather than incidence , as the outcome ; and ( 5 ) were published in a language other than english . a comprehensive and systematic search was conducted using four electronic databases : pubmed , cumulative index to nursing and allied health literature ( cinahl ) , web of science , and proquest ( from their commencement to june 30 , 2012 ) .
since the term ms dates back to the late 1950s , with variations in use as early as the 1920s , the start dates of each of the databases were used as the commencement date for study search : web of science ( 1900 ) , cinahl ( 1952 ) , pubmed ( 1966 ) , and proquest ( 1861 ) .
major keywords used in the search for potentially eligible studies included  metabolic syndrome  (  insulin resistance syndrome ,   syndrome x  ) and  breast cancer  (  neoplasm and breast  ) . using the most recent publication , trials published as duplicate reports ( parallel publications )
an initial cut - off point for the inclusion of studies was not used given the difficulty in establishing such a point , as well as our concern about the potential loss of studies that met our eligibility criteria . at the first screening , one author ( rb ) screened all abstracts and selected articles for full - text examination . at the second level of the study selection process
, two of the authors ( rb and th ) examined the full - text articles and then selected the included studies following mutual discussion and consensus .
two of the authors ( rb and th ) reviewed every study selected and independently extracted data from studies onto electronic coding forms .
attempts were made to contact authors of three of the original studies for missing information [ 13 , 62 , 64 ] , but only one provided the requested information .
after initial coding , the two coders ( rb and th ) reviewed each item for agreement .
using cohen 's kappa ( k ) statistic , the overall interrater agreement rate prior to correcting discrepant items was 0.96 for all included studies .
risk of bias was assessed using a modified version of strengthening the reporting of observational studies in epidemiology ( strobe ) checklist .
the items assessed included ( 1 ) study design , ( 2 ) adjustments for confounders , ( 3 ) selection of participants and their eligibility criteria , ( 4 ) measurement of predictor variables , ( 5 ) breast cancer diagnosis , ( 6 ) study size , ( 7 ) handling of missing data , and ( 8) reasons for nonparticipation of individuals at each stage of the study .
a description of the criteria for risk of bias assessment is shown in table 1 .
two of the authors ( rb and th ) conducted all assessments , independently of each other .
risk estimates were used to examine the association between ms and risk of breast cancer .
these were derived from reported relative risks , odds ratios , hazard ratios , incident rate ratios , or standardized incidence ratios , together with corresponding 95% confidence intervals ( cis ) , from the original studies . where necessary and possible
adjusted risk estimates were pooled for analysis from multivariable models in the original studies . however , for two case - control studies that were included [ 14 , 51 ] , adjusted odds ratios were used because of the lack of the requisite data to convert odds ratios to rrs .
all rr results were pooled using a random - effects model , an approach that incorporates between - study heterogeneity into the model . a z - score two - tailed alpha value  0.05 was considered to be statistically significant . in addition , 95% cis were calculated for each result from each study as well as for pooled estimates .
an alpha level  0.10 for the q statistic was considered to be evidence of statistically significant heterogeneity . while somewhat arbitrary , i values of 25% , 50% , and 75% were considered to represent low , moderate , and high amounts of heterogeneity .
publication bias was assessed using the trim and fill approach of duval and tweedie . in addition , rosenthal 's fail - safe n test was used to compute the number of missing null studies that would be needed to nullify the overall pooled rr as being statistically significant .
influence analysis was conducted with each study result deleted from the model once , in order to examine the effects of each on the overall pooled results .
cumulative meta - analysis , ranked by year , was also conducted in order to examine the accumulation of results over time .
a separate pooled analysis , limited to postmenopausal women , was conducted because studies show that ms in postmenopausal women increases the risk of breast cancer [ 13 , 14 , 43 , 48 , 51 , 62 ] .
in addition , pooled analyses were conducted with the following caveats post hoc : ( 1 ) deletion of results from two case - control studies because odds ratios were used instead of rr [ 14 , 51 ] , ( 2 ) deletion of results from studies that were not prospective cohort designs [ 13 , 14 , 51 ] , and ( 3 ) limiting the results to studies that controlled for four or more of the important confounders ( as listed in table 1 ) [ 14 , 43 , 48 , 51 ] . given the potential for diabetes and diabetes medications to affect breast cancer risk , post hoc data analysis was also conducted with studies that included participants with diabetes and/or taking medications for diabetes , deleted from the model [ 14 , 43 , 64 ] .

 figure 1 presents a flow diagram of the selection of studies for the meta - analysis .
of the 291 studies screened , 47 ( 16.2% ) were selected for full - text review : 25 from pubmed [ 14 , 4355 , 64 , 7483 ] , 17 from the web of science [ 13 , 39 , 63 , 8497 ] , one from cinahl , and four from proquest [ 62 , 99101 ] . eight ( 17.0% ) of the 47 studies that underwent a full - text review met the eligibility criteria [ 13 , 14 , 43 , 48 , 51 , 6264 ] .
one article   presented results for two independent cohorts ; thus each cohort was treated independently .
the study designs included four prospective cohorts [ 48 , 6264 ] , one retrospective cohort , one prospective nested case - control study , and two case - control studies [ 14 , 51 ] .
the baseline year for cohort inception ranged from 1983 to 2004 , with average follow - up ranging between 2.7 and 13.5 years .
six studies conducted analyses on postmenopausal women [ 13 , 14 , 43 , 48 , 51 , 62 ] . the results of each cohort or case - control study were initially reported as a hazard ratio [ 13 , 48 , 63 ] , incidence rate ratio [ 43 , 62 ] , standardized incidence ratio , or odds ratio [ 14 , 51 ] .
methods for exposure assessment , cancer identification , and control of confounders varied across the eight included studies ( table 3 ) .
seven studies identified the outcome ( breast cancer ) through histological reports or medical reports or from a cancer registry [ 13 , 14 , 43 , 48 , 51 , 62 , 64 ] , while one used self - report .
only three studies examined invasive breast cancer cases [ 43 , 48 , 64 ] .
one study also reported on the in situ breast cancer cases but there were only seven such cases in that study .
another study analyzed all breast cancer cases ( in situ and invasive ) as well as invasive cancers separately , and results remained unchanged .
all of the studies were considered to be at low risk for selection of participants and meeting eligibility criteria in addition to providing adequately powered sample sizes .
out of eight studies , a majority were also considered low risk with respect to study design ( six studies ) and measurement of the outcome variable ( seven studies ) . in terms of handling potential confounders ,
half the studies were low risk , three were high risk , and one was unclear risk . missing confounding variables included education , smoking status , alcohol use , family history of cancer , contraceptive use , or hormonal history . similarly , half the studies had objective measurements of predictor variables , while the remainder relied on self - report , and were consequently considered high risk .
four studies deleted the participants with missing variables in their analyses ( high risk ) , while two did not report how they handled missing data .
lastly , six studies were considered high risk because they did not report the reasons for nonparticipation of subjects at each stage of follow - up .
overall , a statistically significant increase of 47% in the risk for incident breast cancer was observed for adult females with ms ( rr : 1.47 , 95% ci , 1.151.87 ; z = 3.13 ; p < 0.002 ; q = 26.28 , p < 0.001 ; i = 69.55% ) ( figure 2 ) . with the exception of one study , all other studies had rr in the direction of increased risk [ 13 , 14 , 43 , 48 , 51 , 62 , 64 ] .
funnel plot results for potential publication bias are shown in figure 3 . using the trim and
fill approach that resulted in two imputations , the risk decreased by 16% but remained significant ( rr : 1.31 , 95% ci , 1.011.70 ) .
null  studies would be needed to nullify the statistically significant association between ms and breast cancer risk in adult females .
no statistically significant outliers were identified ( p = 0.060.82 ) . with each study deleted from the model once , results remained positive and statistically significant ( figure 4 ) .
the pooled rr fell within a range of 20% ( rr = 1.361.56 ) and none of the cis for the point estimates was less than 1.0 .
cumulative meta - analysis , ranked by year , revealed that results have been statistically significant since 2011 ( figure 5 ) .
deleting the two case - control studies from the model , the rr for incident breast cancer for women with ms decreased by 18% but was still statistically significant with moderate heterogeneity ( rr : 1.29 , 95% ci , 1.0031.67 ; z = 1.98 ; p = 0.05 ; q = 14.13 , p = 0.01 ; i = 64.61% ) . when limited to studies with only prospective designs ,
the rr decreased by 30% but remained statistically significant with very low heterogeneity ( rr : 1.17 , 95% ci , 1.011.36 ; z = 2.04 ; p = 0.04 ; q = 4.30 , p = 0.37 ; i = 7.04% ) . when limited to postmenopausal women , breast cancer risk
increased by 34% and was still statistically significant with high heterogeneity ( rr : 1.81 , 95% ci , 1.282.56 ; z = 3.37 ; p = 0.001 ; q = 23.36 , p = 0.001 ; i = 74.32% ) . when limiting the results to studies that controlled for four or more of the important confounders ( as listed in table 1 ) [ 14 , 43 , 48 , 51 ] , breast cancer risk increased by 17% and was statistically significant with moderate heterogeneity (
rr : 1.64 , 95% ci , 1.232.20 ; z = 3.34 ; p = 0.001 ; q = 8.55 , p = 0.07 ; i = 53.21% ) .
lastly , when data were analyzed after deleting from the model those studies that had participants with diabetes or taking medications for diabetes [ 14 , 43 , 64 ] , the rr was slightly larger than the overall finding but the 95% ci included 1.0 ( rr : 1.48 , 95% ci , 0.922.4 ; z = 1.61 ; p = 0.11 ; q = 17.4 , p = 0.02 ; i = 76.96% ) .
the purpose of this aggregate data meta - analysis was to examine the association between ms and the risk for breast cancer in adult females .
overall , the results suggest that there was a modest positive association between ms and risk of breast cancer . this finding is strengthened by the robustness of results from other analyses .
these include ( 1 ) examination for publication bias , ( 2 ) influence analysis with each study being deleted from the model once , ( 3 ) deletion of the two case - control studies with odds ratios from the overall model , ( 4 ) limiting the analysis to prospective designs , ( 5 ) including only postmenopausal women in the analysis , and ( 6 ) limiting the results to studies that controlled for four or more of the important confounders .
in addition , the results from cumulative meta - analysis , ranked by year , indicate an increasingly statistically significant association since 2011 .
in contrast , despite a slightly increased mean rr , overlapping cis were observed when studies that included participants with diabetes or taking medications for diabetes were deleted from the model [ 14 , 43 , 64 ] . however , whether this reduced precision is the result of these specific characteristics or some other factors , for example , loss of power with a reduced number of studies , is not known .
assessment for risk of bias indicated that a majority of studies were at low risk regarding study design , cancer assessment , and sample size .
however , a majority were at high risk or unclear risk in terms of handling of missing data and nonparticipation of subjects at each stage of follow - up .
it is suggested that future studies provide complete information on the handling of missing data and on the nonparticipation of subjects at each stage of follow - up . when limited to postmenopausal women , a stronger association between ms and breast cancer was observed .
this association was stronger in case - control and retrospective cohort study designs compared to prospective cohort study designs .
these findings concur with those from a recent meta - analysis on ms and breast cancer risk in postmenopausal women .
several studies have shown that ms in this group increases the risk of breast cancer [ 43 , 46 , 102 ] , suggesting that the etiology of breast cancer may differ among pre- and postmenopausal women .
first , obese postmenopausal women produce higher levels of estrogens , which in turn increase the biologically available fraction of circulating estradiol by reducing plasma concentration of sex hormone binding globulin ( shbg ) .
low plasma shbg levels are associated with insulin resistance [ 104 , 105 ] and other components of ms [ 106 , 107 ] .
second , adipose tissue produces two adipokines ( cytokine - like factors ) , leptin and adiponectin , that affect breast cancer biology .
higher plasma leptin levels are associated with obesity [ 54 , 57 , 109 ] , insulin resistance [ 110 , 111 ] , and ms [ 112 , 113 ] .
leptin stimulates human breast cancer cell lines , whereas adiponectin acts protectively , inhibiting the growth of these cell lines [ 57 , 108 , 114 ] .
third , insulin has been shown to have a mitogenic effect upon breast cancer cells in vitro through several mechanisms .
moreover , low serum hdl - c concentrations indicate higher circulating bioactive estrogen levels , which in turn may stimulate target breast tissue . the increasing prevalence of ms and its association with breast cancer , among other comorbidities , point toward the critical need to develop public health strategies to manage ms . given the increasingly large global burden of metabolic risk factors ,
risk assessment tools can be developed which incorporate ms as a risk factor for breast cancer .
healthcare providers will then be better equipped to identify high - risk women for primary and secondary prevention .
this study has several strengths . first , to the best of our knowledge , this is the first systematic review and meta - analysis examining the association between ms and risk of breast cancer in all adult women .
the overlapping meta - analysis on metabolic syndrome and breast cancer was confined to postmenopausal women only .
second , a number of other analyses were performed which strengthened the robustness of findings .
third , the results of this study provide direction for future research on this topic .
these include ( 1 ) the different methods used to assess exposure , identify cancer , control for confounders , and define ms , ( 2 ) limiting studies to those published in english , which may have inflated the results , ( 3 ) the relatively small number of studies that met the inclusion criteria , ( 4 ) the inability of some studies to provide raw data for calculating the rr , ( 5 ) the different study designs employed , and ( 6 ) the varied populations studied , including those with diabetes and/or taking medications for diabetes .
most notably and with respect to controlling for adiposity , a potential confounder , two of the included studies controlled for bmi [ 48 , 62 ] but no information was available from the other studies with respect to controlling for bmi or any other obesity - related measures , including such measures of central obesity as waist circumference and waist - to - hip ratio [ 13 , 14 , 43 , 51 , 63 , 64 ] . given the potential association between breast cancer and adiposity , it may be prudent for future studies to control for this potential confounder .
to this point , kabat et al . suggested that some , but not all , studies have reported an association between increased central adiposity and an increased risk for postmenopausal breast cancer .
the inclusion of such information in future studies may be important , given the potential differences in risk according to exposure and disease subtype . in order to inform and undergird a biological rationale for
the observed positive association between ms and breast cancer risk in adult females , future research should comprise analyses based on a standard definition of ms and employ objective and standard biomarkers for assessing each ms component .
. it would be helpful if future studies examined the relationship between ms and breast cancer risk separately in perimenopausal and premenopausal women since breast cancer in women may be estrogen - independent . along those lines , not all studies adjusted for hormone replacement therapy , a potential confounder .
furthermore , they need to examine in situ and invasive cancers separately in relation to metabolic syndrome .
finally , a focus on obese women with respect to ms and breast cancer seems appropriate . in conclusion ,
the overall results of this meta - analysis suggest that there is a modest positive association between ms and risk of breast cancer in adult females .
 
 background . 
 although individual metabolic risk factors are reported to be associated with breast cancer risk , controversy surrounds risk of breast cancer from metabolic syndrome ( ms ) . 
 we report the first systematic review and meta - analysis of the association between ms and breast cancer risk in all adult females . methods . 
 studies were retrieved by searching four electronic reference databases [ pubmed , cumulative index to nursing and allied health literature ( cinahl ) , web of science , and proquest through june 30 , 2012 ] and cross - referencing retrieved articles . 
 eligible for inclusion were longitudinal studies reporting associations between ms and breast cancer risk among females aged 18 years and older . 
 relative risks and 95% confidence intervals were calculated for each study and pooled using random - effects models . 
 publication bias was assessed quantitatively ( trim and fill ) and qualitatively ( funnel plots ) . 
 heterogeneity was examined using q and i2 statistics . 
 results . representing nine independent cohorts and 97,277 adult females , eight studies met the inclusion criteria . a modest 
 , positive association was observed between ms and breast cancer risk ( rr : 1.47 , 95% ci , 1.151.87 ; z = 3.13 ; p = 0.002 ; q = 26.28 , p = 0.001 ; i2 = 69.55% ) . no publication bias was observed . 
 conclusions . 
 ms is associated with increased breast cancer risk in adult women . 