triple - negative breast cancers ( tnbcs ) lack expression of the steroid receptors estrogen ( er ) and progesterone ( pr ) and the tyrosine kinase human epidermal growth factor receptor 2 ( her-2 ) . therefore , tnbcs are a diagnosis of exclusion , typically characterized by upregulation of cytokeratins 5 , 14 , and 17 and elevation of the epidermal growth factor receptor ( egfr ) [ 13 ] .
studies estimate that approximately 1520% of breast cancers meet these criteria [ 46 ] . compared to other breast cancer subtypes ,
tnbcs are typically aggressive , invasive ( ductal , medullary , or metaplastic ) , grade iii tumors with high rates of mitotic division , of which approximately half contain a high rate of p53 mutations . for these reasons
, they account for a disproportionately high percentage of metastases , distant recurrence , and death among patients with breast cancer .
metastases in tnbcs are most common to visceral organs including liver , lungs , and central nervous system . as a diagnosis of exclusion ,
tnbc overlaps considerably with basal - like breast cancer ( blbc ) although differences between the two subtypes exist , especially at a genetic level .
other molecular subtypes defined by gene expression patterns include luminal a , luminal b , her-2-enriched group , and claudin - low , all of which may include tnbcs to some extent [ 8 , 9 ] .
tncbs are most common among premenopausal women , especially those of african american descent [ 46 , 10 ] . in addition , tnbcs are common among patients with brca1 mutations [ 11 , 12 ] .   since the first molecular characterization of tnbcs in the literature in 2005 , the topic has quickly emerged as an active area of research .
while initial studies focused on molecular and clinical characterizations of patients with the diagnosis , more recent studies have identified subgroups of patients with tnbc , proposed molecular mechanisms that may contribute to tumorigenesis , and explored potential therapeutic interventions for patients . in this paper
, we examine the connection between tnbc and the metabolic syndrome , which consists of central obesity , insulin resistance , impaired glucose tolerance , dyslipidemia , and hypertension .
our analysis of the literature will encompass in vitro and in vivo studies in cell lines and mouse models of tnbc , respectively , as well as clinical studies examining epidemiology and treatment of tnbc .
obesity , which is associated with insulin resistance and type 2 diabetes mellitus ( dm ) , is an established risk factor for cancer incidence . in a meta - analysis of 141 articles , body mass index ( bmi )
was positively associated with an increased incidence of postmenopausal breast cancer , along with colon , endometrial , esophageal , gallbladder , pancreas , renal , thyroid cancers , leukemia , multiple myeloma , and non - hodgkin 's lymphoma in women .
the results were less clear , however , for premenopausal breast cancer as a positive association between obesity and premenopausal breast cancer was found in asia - pacific women ( risk ratio ( rr ) = 1.16 ; 95% ci , 1.011.32 ) , while inverse relations were reported in north american women ( rr = 0.91 ; 95% ci , 0.850.98 ) and european and australian women ( rr = 0.89 ; 95% ci , 0.840.94 ) these findings suggest that different subpopulations of women possess different risk factors for breast cancer . it may also suggest that bmi is not an ideal measure of adiposity .
instead , other measures such as waist - to - hip ratio ( whr ) or waist circumference , which are specific measures of central or abdominal adiposity , may be preferential to assess cancer risk .
two meta - analyses that examined a correlation between elevated whr and risk of breast cancer in premenopausal women reported positive associations [ 15 , 16 ] .
the study by connolly et al . reported that elevated whr was associated with a 79% ( summary risk ( sr ) = 1.79 ; 95% ci , 1.222.62 ) increased risk of breast cancer for premenopausal women and a 50% ( sr = 1.50 ; 95% ci , 1.102.04 ) increased risk for postmenopausal women .
similarly , the study by harvie et al . reported that small whr was associated with a 37% decreased risk ( rr = 0.63 , 95% ci , 0.450.88 ) in premenopausal women only after adjusting for bmi .
the authors hypothesized that general obesity may not modulate risk , but central obesity increases risk in premenopausal women .
in contrast , the authors reported that general obesity and not central obesity increased cancer risk in postmenopausal women .
this interesting result led the authors to hypothesize that insulin resistance and insulin - like growth factors , which are associated with central obesity , may play a larger role in modifying breast cancer risk for premenopausal women , while estrogen may play a greater role in postmenopausal breast cancer .  
while the link connecting obesity and incidence of all types of breast cancers is well established , the data examining obesity and tnbc are much less prevalent . in the carolina breast cancer study , whr was compared between the highest ( 0.84 ) and lowest ( < 0.77 ) groups in relation to blbc . across all women
, there was an increased risk ( odds ratio ( or ) = 2.3 ; 95% ci , 1.43.6 ) for developing blbc with higher whr .
premenopausal women ( or = 1.8 ; 95% ci , 1.03.4 ) and postmenopausal women ( or = 2.7 ; 95% ci , 1.35.4 ) with high whr both had elevated risk of developing breast cancer compared to the lowest whr group .
weight gain in women as reported since fifth grade was highest in african american women in this sample .
in contrast , no significant trend was reported for bmi and risk of breast cancer . a 2008 study examining 620 predominantly white women in rural appalachia ,
117 of whom had tnbc , reported a significant association between obesity and incidence of tnbc . in this sample ,
approximately 50% of patients with tnbcs were obese as compared to 36% of non - tnbcs .
the preponderance of evidence suggests an association between tnbc and obesity when obesity is defined as an elevated whr , but more contradictory evidence exists when using bmi as a measure of obesity . clearly , the conflicting results warrant additional research .
future epidemiological studies would benefit from measurement of all three receptor markers and studies that concurrently examine multiple definitions of obesity . a common corollary of metabolic syndrome
a 2007 meta - analysis of twenty studies estimated a 20% increased risk of breast cancer for women with type 2 dm ( rr = 1.20 ; 95% ci , 1.121.28 ) .
for tnbc , one study reported a significant relation with 58% of patients with tnbc possessing a comorbid diagnosis of metabolic syndrome compared to 37% of patients without tnbc in a sample of 176 individuals using criteria of the national cholesterol education program and 52% compared to 34% using criteria of the american association of clinical endocrinologists .
in addition , a 2011 study reported a 75% increase in the risk of postmenopausal breast cancer ( rr = 1.75 ; 95% ci , 1.372.22 ) for women who were found to have at least three of the four components of metabolic syndrome .
however , the carolina breast cancer study reported no elevated prevalence of type 2 dm in tnbc compared to other breast cancer subtypes . recently ,
epidemiological studies have associated dyslipidemia and hypertension with breast cancer risk . in a prospective study examining all - cancer incidence of 1,189,719 korean men and women , kitahara et al . reported a positive association between total cholesterol and breast cancer risk in women ( hazard ratio ( hr ) = 1.17 ; 95% ci , 1.031.33 ) .
the researchers compared individuals with total cholesterol 240  mg / dl to individuals with cholesterol  < 160  mg / dl and adjusted for cigarette smoking , alcohol consumption , bmi , fasting serum glucose , hypertension , and physical activity . in addition , hypertension was independently predictive of breast cancer risk in a sample of 3,869 postmenopausal women with breast cancer as compared to 4,082 controls ( or = 1.19 ; 95% ci , 1.071.33 ) .
another study reported a 23% increased risk of breast cancer for hypertensive women . however , after adjustment of confounders including bmi , the elevated risk was no longer significant ( hr = 1.14 ; 95% ci , 0.931.40 ) .  
epidemiological studies suggest a positive association between the metabolic syndrome as a whole , along with many of its individual components , and breast cancer risk .
the many confounding variables that may mediate this effect need to be considered in order to determine whether this is a causative effect .
further studies should also address how changes in components of metabolic syndrome , such as weight , affect incidence of disease , and treatment outcomes after initial diagnosis of tnbc .
larger sample sizes will determine whether subpopulations of patients with tnbc ( e.g. , pre- versus postmenopausal women ) possess unique clinical and molecular characteristics .
in addition to exploring risk factors that influence incidence of tnbc ( primary prevention ) , it is also essential to understand factors that influence recurrence of tnbc ( secondary prevention ) .
compared to other subtypes of breast cancer , tnbcs are more often diagnosed as aggressive , invasive , grade iii , and lymph - node positive tumors .
these outcomes are predictive of increased morbidity and mortality . in addition , tnbcs have a high rate of recurrence with visceral metastases compared to other subtypes of breast cancer , especially within the first five years after diagnosis . after five years , the risk of recurrence drops dramatically .   
obese patients with breast cancer have more frequent recurrence and worse prognosis as compared to lean patients . in a sample of 495,477 u.s .
women , increasing bmi was significantly associated with increased death rates for breast cancer . as compared to the lowest bmi group ( 18.524.9 )
, there was an elevated risk of 34% for bmi of 25.029.9 ( rr = 1.34 ; 95% ci , 1.231.46 ) , 63% for bmi of 30.034.9 ( rr = 1.63 ; 95% ci , 1.441.85 ) , 70% for bmi of 35.039.9 ( rr = 1.70 ; 95% ci , 1.332.17 ) , and 112% for bmi  40.0 ( rr = 2.12 ; 95% ci , 1.413.19 ) of dying of breast cancer .
furthermore , in a sample of 18,967 patients in denmark with early - stage breast cancer , bmi at diagnosis was correlated with disease prognosis .
kg / m had a 46% higher risk of distant metastases ( hr = 1.46 ; 95% ci , 1.111.92 ) after 10 years and 38% increased risk of mortality from breast cancer ( hr = 1.38 ; 95% ci , 1.111.71 ) ) as compared to patients with bmi < 25  kg / m .
the authors also suggested that adjuvant chemotherapy and endocrine therapy were less effective over time periods greater than 10 years for patients with bmi > 30 although it was unclear whether this effect was mediated by poor responsiveness to treatment or differences in biology .
even though obese patients were more likely to present with advanced tumors in terms of size and spread to lymph nodes , obesity was still an independent predictor after controlling for these confounders .
the study measured bmi after diagnosis of tnbc and then counted the number of recurrences and deaths . after controlling for clinically significant factors , no significant relation was found between bmi and overall survival ( hr = 0.94 ; 95% ci , 0.541.64 ) or recurrence - free survival ( hr = 0.81 ; 95% ci , 0.491.34 ) . in a sample of 1,169 patients diagnosed with invasive breast cancer , the relationship between general obesity and response to neoadjuvant chemotherapy was examined . when comparing overweight ( bmi 25 to < 30  kg / m ) and obese ( bmi  30  kg / m ) groups to the normal / underweight group ( bmi < 25 ) , a significant association was present for pathologic complete response to neoadjuvant chemotherapy ( or = 0.67 ; 95% ci , 0.450.99 ) in the normal / underweight group .
while high bmi was associated with worse overall survival , no significant effects were seen for breast - cancer specific or progression - free survival . finally , although data linking risk of recurrence and mortality in patients with hypertension and tnbc are limited , a 2011 study retrospectively examined the use of beta blockers on prognosis for patients with breast cancer .
after adjustment for a number of covariates , patients with tnbc who were taking beta blockers had significantly improved relapse - free survival ( hr = 0.30 ; 95% ci , 0.100.87 ) , and while overall survival was improved ( hr = 0.35 ; 95% ci , 0.121.00 ) , it only approached a significance level ( p = 0.05 ) .
similar findings were also reported for non - tnbc subtypes . a number of epidemiological studies have suggested that physical activity and weight loss are inversely related breast cancer risk and recurrence .
the women 's healthy eating and living ( whel ) study prospectively examined 1,490 women with breast cancer .
the authors reported that performing exercise equivalent to walking 30  min , six days per week , and consuming 5 daily servings of fruits and vegetables decreased mortality by 46% ( hr = 0.56 ; 95% ci , 0.310.98 ) .
while er+ tumors were associated with decreased mortality with these lifestyle interventions ( p < 0.05 ) , no significant effect was observed for er , pr tumors ( p = 0.40 ) .
to the best of our knowledge , the largest study to date examining the link between physical activity and invasive breast cancer was a meta - analysis of 12,108 patients , which included six studies . while physical activity prior to diagnosis had no effect on breast cancer deaths across all patients , physical activity after diagnosis reduced breast cancer deaths by 34% ( hr = 0.66 , 95% ci , 0.570.77 ) and disease recurrence by 24% ( hr = 0.76 , 95% ci , 0.660.87 ) .
postdiagnosis exercise only provided significant benefits for patients with bmi  25  kg / m .
interestingly , physical activity after diagnosis reduced breast cancer deaths by 50% ( hr = 0.50 , 95% ci , 0.340.74 ) for er+ tumors with no significant effect for patients with er tumors . when looking at the individual studies that composed the meta - analysis , the studies that examined postdiagnosis physical activity were prospective , observational , and questionnaire - based studies , while those that examined prediagnosis physical activity had case - control designs [ 3237 ] .
while the definition of physical activity varied somewhat from study to study , the studies generally defined physical activity as moderate recreational activity , and for the purpose of their analyses , the authors combined these forms of exercise into metabolic equivalent task ( met ) hours per week .
examples of moderate physical activity included walking , jogging , running , biking , swimming , tennis , calisthenics / aerobics , and squash / racquetball .
one study included in the meta - analysis specifically examined the relation between risk reduction of breast cancer and duration of exercise . in a sample of 2,987 women diagnosed with breast cancer
compared to women who performed the equivalent of walking at an average pace less than 3 met - hours per week , there was a nonsignificant 20% risk reduction of death from breast cancer for 3 to 8.9 met - hours per week ( rr = 0.80 ; 95% ci , 0.601.06 ) , a significant 50% risk reduction for 9 to 14.9 met - hours per week ( rr = 0.50 ; 95% ci , 0.310.82 ) , 44% risk reduction for 15 to 23.9 met - hours per week ( rr = 0.56 ; 95% ci , 0.380.84 ) , and 40% risk reduction for 24 or more met - hours per week ( rr = 0.60 ; 95% ci , 0.400.89 ) .
this study , however , did not find a significant effect for exercise , even for 9 or more met - hours per week , for er , pr tumors .  
these studies provide an insight on the role of physical activity as a potentially beneficial breast cancer treatment that may be used in conjunction with existing radiation and chemotherapy treatments [ 3237 ] . although studies explicitly targeting patients with tnbc have not been performed , a potential mechanism behind this link may be decreased concentrations of estrogen via reduction in body fat or decreased androgens via increase in globulins that bind testosterone .
in addition to exercise , two large randomized studies have examined whether diet interventions are effective in reducing breast cancer recurrence and mortality [ 39 , 40 ] .
the women 's intervention nutrition study ( wins ) examined 2,437 women with breast cancer .
the randomized study involved a dietary intervention group with a goal of reducing calories from fat to 15% without compromising nutrition compared to control with median followup of 60 months .
when comparing relapse events between the two groups , relapse was lower in the intervention group as compared to the control group ( hr = 0.76 ; 95% ci , 0.600.98 , p = 0.077 for stratified log rank and p = 0.034 for adjusted cox model analysis ) .
the authors reported a trend for a stronger effect for dietary fat reduction for hormone receptor - negative cancers ( hr = 0.58 ; 95% ci ,   0.370.91 ) compared to er+ tumors ( hr = 0.85 ; 95% ci , 0.631.14 ) , although no significant effect was found ( interaction test , p = 0.15 ) .
one of the criticisms of the wins study was the fact that the intervention group lost about 6 pounds more than the control arm over the duration of the study ( p = 0.005 ) .
as a result , it was unclear whether the outcomes were due to decreased weight or decreased fat intake . furthermore , the dietary intervention was relatively strict , making it hard to implement in everyday practice .
in addition , the whel study evaluated the potential benefit of physical activity and a diet rich in vegetables and fruit in breast cancer survivors .
the arm randomized to a diet rich in vegetables , fruit , and fiber , but low in fat did not have a significantly lower mortality ( hr = 0.91 ; 95% ci , 0.721.15 ) or a lower incidence of second invasive breast cancer ( hr = 0.96 ; 95% ci , 0.801.14 ) during a 7.3-year follow - up period . in this study ,
the intervention and comparison groups had an average weight difference of 1-kg or less based on measurements at baseline , 1 year , 2 or 3 years , 4 years , and 6 years . in an analysis of the comparison group only , consuming 5 daily servings of fruits and vegetables and performing exercise equivalent to walking 30  min , six days per week at baseline was associated with lower mortality .
no effect , however , was reported in the randomized trial based on physical activity at baseline for additional breast cancer events or all - cause mortality .
these conflicting findings warrant further research , especially to assess diet interventions for patients with tnbc .    
alcohol consumption also appears to moderate recurrence and mortality for breast cancer survivors . in a recent study of 1,897 individuals , consumption of three to four alcoholic drinks or more per week
was associated with a 35% ( hr = 1.35 ; 95% ci , 1.001.83 ) increased risk of breast cancer recurrence and 51% ( hr = 1.51 ; 95% ci , 1.002.29 ) increased risk of death due to breast cancer .
no difference was found between er+ versus er subgroups although the authors noted that this lack of effect may have been due to a small sample size of patients with er tumors .
further studies will be important to assess whether different subtypes of breast cancer are affected differently by diet and alcohol in order to further probe the mechanism of these effects .
in particular , upregulation of insulin has been hypothesized to directly increase proliferation of breast tissue and breast cancer cells .
a 2009 study , which measured insulin at baseline and at 1 , 3 , and 6 years of followup , reported a hr of 2.22 ( 95% ci , 1.393.53 ) for incidence of breast cancer in postmenopausal women when comparing the highest baseline insulin concentration group to the lowest group .
another study demonstrated that a high homeostatic model assessment score , which is associated with serum levels of insulin and glucose , was correlated with increased breast cancer mortality in a sample of 527 women .
similarly , a 2011 study of 604 women in the health , eating , activity , and lifestyle ( heal ) study measured serum c - peptide , a marker of insulin secretion , three years after diagnosis .
an increased c - peptide concentration of 1  ng / ml was associated with a 35% increased risk of death from breast cancer ( hr = 1.35 ; 95% ci , 1.021.87 ) .  
collectively , these data suggest that hyperglycemia and hyperinsulinemia are associated with poor prognosis for patients with breast cancer . in contrast , a 2007 case - control study examining blood samples in predominantly premenopausal women reported that increased levels of insulin and c - peptide were not risk factors for breast cancer .
baseline hemoglobin a1c ( hba1c ) levels among 3,003 patients were examined for recurrence and all - cause mortality .
the authors reported a significant increase in all - cause mortality after adjustment for confounders for women with hba1c 7.0% as compared to < 6.5% ( hr = 2.35 ; 95% ci , 1.563.54 ) .  
the actions of insulin may also occur indirectly via decreased availability of globulin and insulin - like growth factor- ( igf- ) binding proteins and increased blood concentration of testosterone , estrogens , or igfs .
elevated concentrations of unbound estradiol and testosterone have been associated with increased breast cancer risk in pre- and postmenopausal women [ 4750 ] .
insulin also inhibits sex hormone - binding globulin ( shbg ) production and increases the levels of igf - i in blood , which results in increased mitogenic activity .
this link is consistent with approximately 50% of breast cancer tumors overexpressing igf - i receptor .
a recent laboratory study found that seven cell lines that serve as models of tnbc expressed igf receptors .
surprisingly , expression was at similar levels to er+ cell lines even though type i igf receptor levels are increased by estrogen in er+ cell lines . in all cases ,
although studies have reported a positive association between type 2 dm and breast cancer , a potential confounding variable in establishing this relation is treatment regimen .
insulin has recently been implicated to have cancer promoting effects , while recent evidence suggests metformin to have cancer protecting effects in patients with type 2 dm .
insulin glargine use , especially when prolonged , may increase the incidence of breast cancer . in one study , this effect was especially prominent for individuals who had received insulin for an average of 5.6 years before starting insulin glargine ( hr = 2.7 ; 95% ci , 1.16.5 ) .
in contrast , metformin has been shown to inhibit proliferation and colony formation of tnbc cells in vitro .
metformin resulted in decreased tumor growth if injected in tnbc tumor xenograft mice and decreased tumor incidence if added before injecting tnbc cells . while the molecular mechanism of how metformin reduces breast cancer incidence and survival is unclear , potential mechanisms include ( 1 ) acting as a general growth inhibitor , ( 2 ) reducing serum insulin levels , and ( 3 ) reducing body weight [ 54 , 57 ] .
interestingly , the drug only exhibited an antiapoptotic effect in tnbc cell lines , an effect which was not present for luminal a , b , and her-2 subtypes .
recently , observational studies were performed suggesting that metformin reduces the risk of breast cancer in humans . in one study ,
metformin use was associated with a 38% lower incidence of er+ , pr+ tumors in postmenopausal women with type 2 dm .
no significant effect was demonstrated for er , pr tumors , however , although the sample size for tnbcs was limited .
in addition , prospective studies are under way on the role of metformin in breast cancer recurrence .
further studies are necessary to determine whether elevated levels of insulin and c - peptide are risk factors for women with tnbc , as well as to elucidate the mechanism behind this association .
leptin is the product of the obesity ( ob ) gene and is primarily synthesized and secreted by adipose tissue , with increasing adiposity associated with higher circulating leptin levels . .
leptin helps regulate food intake and metabolism via its actions on the arcuate nucleus of the hypothalamus .
it is hypothesized that leptin resistance in obese individuals may be analogous to insulin resistance in diabetics .
this resistance has been proposed to develop via impaired transport of leptin across the blood brain barrier and circumventricular organs and leptin receptor signal attenuation .
clinical studies have reported a positive association between circulating blood leptin and breast cancer risk with particular elevation of mrna expression in adipocytes in close proximity to the tumor .   on a molecular level , it has been hypothesized that elevated leptin expression in epithelial mammary cells may promote tumorigenesis via mechanisms including cell proliferation ( aromatase , mapk , stat3 , and cyclin d1 ) , angiogenesis ( vegf ) , apoptosis ( p53 and caspase 9 ) , cell - cycle regulation ( p21 ) , and cell survival ( akt ) in breast cancer cell lines . in tnbc cell lines , a study by saxena et al . reported that leptin directly increased activity of the igf - i receptor .
in addition , bidirectional crosstalk between leptin and igf - i upregulated egfr promoting proliferation and migration of tnbc cells .
the study further reported that using the egfr inhibitors , lapatinib and erlotinib , in an in vitro model system for metastasis after application of leptin and igf - i reduced invasion and migration of breast cancer cells .
collectively , these data suggest a possible therapeutic route for treatment of tnbc with egfr inhibitors , because up to 70% of tnbcs overexpress egfr .
in addition to leptin and igf - i , a 2011 study by burga et al . reported another potential mechanism for elevated levels of egfr protein .
after rna knockdown of brca1 in mammary epithelial cells , egfr protein was upregulated due to transcriptional modification and posttranslational stabilization of egfr .
this is important to our understanding of tnbcs , because brca1 mutations are highly correlated with tnbcs .
interestingly , egfr inhibition with erlotinib in female brca1 knockout mice , in vivo , prevented or delayed development of er , but not er+ tumors . however , the treatment was not effective in shrinking the tumor after tumorigenesis .  
a causal link between leptin and breast cancer is supported by animal studies in which obese mice that overexpressed transforming growth factor - alpha ( tgf- ) , but were deficient in leptin , did not develop mammary tumors , while heterozygous and homozygous wild type leptin mice developed tumors in 50% and 67% of cases , respectively . however , these findings were difficult to interpret , because leptin deficient mice possessed limited mammary tissue .
further studies in mouse models , in vivo , suggest a therapeutic potential for leptin receptor , antagonists . in a recent study of 69 tnbc tumors ,
92% of breast tumors expressed leptin receptor and 86% expressed leptin . in this study , the peptide allo - aca , a leptin receptor antagonist , extended survival time by up to 80% in a tnbc mouse xenograft model , in vivo .
clinical studies are needed to determine whether leptin antagonists may hold promise as a therapy in humans , especially in obese patients who overexpress leptin .
clinical trials in humans are currently underway to test the efficacy of egfr inhibitors in tnbc .
these studies have focused on using cetuximab , a humanized antiegfr igg1 antibody in conjunction with ixabepilone , cisplatin , carboplatin , or a taxane .
12 patients with metastatic tnbc were treated with either paclitaxel or docetaxel with cetuximab weekly . of the eleven patients assessable to followup , nine ( 82% ) exhibited decrease in size of metastasis , but three ( 27% ) developed brain metastasis during treatment ( 133 ) .
other studies by carey et al . and o'shaughnessy et al . have reported therapeutic value of using egfr inhibitors in conjunction with other chemotherapy agents including ( 1 ) carboplatin plus cetuximab and ( 2 ) irinotecan and carboplatin , plus cetuximab [ 70 , 71 ] .
the study by carey et al . compared cetuximab alone to carboplatin plus cetuximab in patients with tnbc metastases .
of the 71 patients who received both drugs , 13 ( 18% ) responded to treatment as compared to only 2 of 31 ( 6% ) of patients who received cetuximab alone .
in addition , the preliminary results of the randomized phase ii study of metastatic patients with tnbc by o'shaughnessy et al . reported no improvement in objective response rate ( orr ) , progression - free survival , and overall survival across all patients with metastatic disease when comparing cetuximab in conjunction with irinotecan and carboplatin as compared to irinotecan and carboplatin .
however , subset analysis of revealed that orr was increased in metastatic patients with tnbc when using all three drugs ( 19 of 39 ; 49% ) as compared to only irinotecan and carboplatin ( 10 of 33 ; 30% ) . these findings may suggest a therapeutic benefit of using egfr inhibitors for a subset of patients with tnbc . larger experimental and control groups and increased number of follow - up years will benefit our understanding of the potential for these treatments .
adiponectin , a protein secreted exclusively by adipose tissue , is an endogenous insulin sensitizer .
after controlling for bmi , studies have reported that women with increased adiponectin concentrations possessed a 65% reduced risk for breast cancer [ 7274 ] . in another sample of 527 women diagnosed with stage i  iiia breast cancer , adiponectin levels above 15.5  g / ml were associated with improved breast cancer survival ( hr = 0.39 ; 95% ci , 0.150.95 ) .
the authors reported prognostic value of adipokines in er , pr tumors but not er+ , pr+ tumors ( p for trend = 0.027 ) .
patients with low adiponectin levels as defined by the first quartile in the study had a significantly increased likelihood of cancer recurrence as compared to patients in the fourth quartile ( hr = 2.82 ; 95% ci , 1.037.68 ) .
these results were significant even after adjustment for bmi and homeostasis model assessment scores for insulin resistance .
we recently evaluated the role of adiponectin pathway single nucleotide polymorphisms ( snps ) in breast cancer risk .
we performed a case - control study on 733 breast cancer cases and 839 controls and genotyped 10 haplotype - tagging snps of adiponectin ( adipoq ) and the type i adiponectin receptor   ( adipor1 ) genes .
we showed that two functional polymorphisms of adipoq , and one functional polymorphism which has been shown to alter mrna levels of adipor1 was significantly associated with risk of breast cancer . when categorized by signaling status ,
low adiponectin signalers had a 6.56-fold increase in breast cancer risk ( 95% ci , 0.7854.89 ) , and intermediate adiponectin signalers had a 4.16-fold increase in risk ( 95% ci , 0.4935.19 ) compared to high signalers ( p for trend = 0.001 ) .
although these data are preliminary , they provide evidence for a significant role for adiponectin in predicting breast cancer risk .  
the mechanisms underlying the association between adiponectin and breast cancer risk have been studied by several investigators .
components of the adiponectin signaling pathway have been implicated in breast tumorigenesis . more specifically , a number of compounds related to cell proliferation ( aromatase , mapk , and cyclin d1 ) , apoptosis ( bcl2 and caspase 8) , cell - cycle regulation ( ampk ) , and cell survival ( akt ) have been implicated to mediate tumorigenesis in breast cancer cell lines . while adiponectin has been shown to have an antiproliferative effect on cell growth in both er+ and er cell lines , the dominant mechanisms responsible for these effects in er+ and er cell lines are likely different .
for example , in mcf-7 cells , 24 hour treatment with adiponectin resulted in an antiproliferative effect lasting up to 96 hours . whether adiponectin induces cell apoptosis is controversial and depends on the particular breast cancer cell line and the duration of the adiponectin incubation period .
one study reported that increased cleavage of poly ( adp - ribose ) polymerase ( parp ) , which serves as an early apoptotic biomarker , was only detected in er+ cell lines .
other studies have reported that adiponectin inhibits aromatase and estrogen receptor activity , mechanisms which would primarily act on er+ tumors . collectively , these data suggest that adiponectin acts via multiple signaling pathways with different mechanisms predominating in er+ and er cell lines .
animal studies have demonstrated that overexpression of adiponectin , both locally and systemically , reduces mammary tumor size .
the proposed mechanisms linking low adiponectin levels and breast carcinogenesis are ( 1 ) interaction with insulin [ 60 , 81 ] , ( 2 ) interaction with leptin , ( 3 ) inhibition of tnf- in macrophages , ( 4 ) binding of fibroblast growth factor and platelet - derived growth factor - beta polypeptide , ( 5 ) inhibition of nuclear factor b , and ( 6 ) promotion of angiogenesis .
further research exploring the link between adiponectin levels over time and breast cancer risk is needed in order to elucidate dominant mechanisms in different breast cancer subtypes .
furthermore , monitoring changes in adiponectin levels in conjunction with different pharmacological and/or behavioral modifications such as diet or exercise in human patients may contribute to a better understanding of its role in tnbc .
finally , treatments aimed at increasing adiponectin levels should be explored for their potential therapeutic and preventive benefit in breast cancer .
considerable evidence links the components of metabolic syndrome , including central obesity , insulin resistance , glucose intolerance , dyslipidemia , and hypertension , with the different breast cancer subtypes .
although data on the connection between tnbc and the metabolic syndrome are limited , several studies have provided evidence for this association .
studies have reported an association between elevated abdominal obesity , as defined by a high whr , and increased incidence of tnbc , but the evidence for bmi is more contradictory [ 17 , 18 ] .
in addition , while type 2 dm and insulin resistance are associated with elevated breast cancer incidence , early evidence suggests that tnbcs do not have increased prevalence of type 2 dm compared to non - tnbcs . in terms of disease progression
, obesity is associated with worse prognosis and increased recurrence across all breast cancer subtypes [ 25 , 26 , 28 ] .
hyperglycemia and hyperinsulinemia have also recently been associated with increased incidence and poor prognosis [ 4244 ] .
additionally , behavioral modifications including moderate physical activity , a diet rich in fruits , vegetables , and micronutrients , and reduced alcohol consumption show promise across all breast cancer subtypes [ 3237 , 39 , 41 ] .
it remains to be seen whether these alternative therapies may prove useful in conjunction with chemotherapy for patients with tnbc .  
molecular mechanisms of how these components of metabolic syndrome may mediate tumorigenesis and disease progression have been proposed .
insulin may mediate breast cancer risk via both direct and indirect effects , resulting in increased concentration of androgens and estrogens , along with increased concentration of igf - i [ 4753 ] .
leptin and adiponectin , which are both secreted by adipose tissue and often by breast tumors , act via a number of downstream signaling pathways involved in cell proliferation , apoptosis , cell - cycle regulation , angiogenesis , and cell survival .
it is likely that normal cells must maintain a fine balance between leptin and adiponectin in order to maintain proper cell and tissue homeostasis , and the components of metabolic syndrome appear to disrupt this balance by increasing leptin and decreasing adiponectin levels [ 61 , 62 , 64 ] .
in addition , insulin , igf - i , and egfr may play a pivotal role in mediating the potential interactions between these two hormones [ 65 , 66 ] .  
we propose that components of the metabolic syndrome and the insulin - leptin - adiponectin axis play a pivotal role in the pathogenesis and progression of tnbc ( figure 1 ) . at present , treatments for tnbc are limited compared to other subtypes of breast cancer , because these tumors are resistant to hormone therapy and drugs that target the her-2 protein .
clinical trials have shown efficacy of treatments such as chemotherapy , anti - egfr drugs , antiangiogenic drugs , and parp inhibitors in the treatment of tnbc .
lifestyle factors including diet , reduced alcohol consumption , and physical activity , which may modulate components of the metabolic syndrome , may also play a pivotal role in decreasing incidence and risk of recurrence of tnbc .
trials that incorporate agents such as metformin or leptin antagonists as well as other therapies that modify the insulin - leptin - adiponectin axis may prove very beneficial for prevention and treatment of tnbc .
 triple - negative breast cancers ( tnbcs ) are aggressive tumors with poor prognosis compared to other breast cancer subtypes . 
 the evidence linking tnbc with the metabolic syndrome , which consists of central obesity , insulin resistance , impaired glucose tolerance , dyslipidemia , and hypertension , has emerged from clinical studies and experiments using cell lines and mouse models . 
 epidemiological studies have associated abdominal obesity with increased incidence of tnbc . additionally , insulin resistance , dyslipidemia , and hypertension are associated with increased incidence of breast cancer across all subtypes . 
 the insulin - leptin - adiponectin axis has been implicated mechanistically in breast cancer tumorigenesis . 
 specifically , increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cell proliferation , survival , cell - cycle regulation , and angiogenesis . 
 insulin , insulin - like growth factor i ( igf - i ) , and epidermal growth factor receptor ( egfr ) may mediate interactions between these two hormones . further research will facilitate the development of targeted therapeutics and programs to modify lifestyle factors to modulate the insulin - leptin - adiponectin axis for tnbc . 
1. Introduction
2. Risk Factors for TNBC 
3. Risk of Recurrence and Mortality in TNBC
4. Insulin and TNBC
5. Leptin and TNBC
6. Adiponectin and TNBC
7. Conclusions