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Endocrinology. Jun 2009; 150(6): 2537–2542.
Published online Apr 16, 2009. doi:  10.1210/en.2009-0070
PMCID: PMC2689796

Obesity and Breast Cancer: The Estrogen Connection

Abstract

There is now substantial evidence that overweight and/or obesity and/or weight gain are risk factors for the development of postmenopausal breast cancer. In addition, obesity and/or elevated body mass index at breast cancer diagnosis has a negative impact on prognosis for both premenopausal and postmenopausal women. Therefore, understanding the mechanism of how obesity affects the mammary tumorigenesis process is an important health issue. Elevated serum estrogen levels as well as enhanced local production of estrogen have been considered primary mediators of how increased body weight promotes breast cancer development in postmenopausal women. Here, we provide an overview of estrogen’s relationship with both obesity and breast cancer as separate entities. Human and relevant preclinical studies are cited. In addition, other growth factors that may be involved in this relationship are considered.

Epidemiological studies indicate that overweight and/or obesity, usually reflected by body mass index (BMI) [BWI = weight (kg) ÷ height (m2)], is a risk factor for the development of postmenopausal breast cancer (1,2,3,4,5,6,7,8,9,10,11,12,13,14). Although obesity in premenopausal women has been associated with a decreased breast cancer risk, this may be unique to industrialized societies (15) and may be applicable only to younger obese women (16). More recently a prospective study conducted in Norway confirmed the protective effect of overweight and obesity for premenopausal breast cancer, but not for women with a family history of the disease (17).

Weight gain in adulthood also has been implicated as an important determinant of breast cancer risk (18,19,20,21,22,23,24,25,26,27,28). In fact a recent publication assessing breast cancer risk factors listed BMI and weight gain between the ages of 20 and 50 yr as second only to Gail Model parameters [quantitative breast density, free estradiol, parity (yes/no), and age of menopause] in importance (29). It has been suggested that body fat may be a better predictor of postmenopausal breast cancer risk than either body weight or BMI (30), and body fat distribution may also impact breast cancer risk (31,32,33). However, when conducting large-scale studies, measurements of body fat and body fat distribution are not as easily obtained as height and weight, which can then be used for calculating BMI.

Obesity also is associated with greater tumor burden in women diagnosed with breast cancer (34,35) and with higher grade tumors (36,37,38). For both premenopausal and postmenopausal women, overweight/obesity is associated with poorer prognosis and/or increased mortality (14,35,36,39,40,41,42,43). One recent study indicated that the BMI effect on mortality in postmenopausal women may be of greater impact in younger women (44).

With the incidence of overweight and obesity increasing throughout the world, the number of women at risk for developing breast cancer will also increase. For example, a quick calculation based on U.S. Census Bureau data indicates that there are about 45 million women in the United States between the ages of 45 and 75 yr, and it is estimated that 40% of them are obese. That results in approximately 18 million women at increased risk for breast cancer! This does not count those considered to be overweight, whose risk is also increased by their body weight status. Thus, a clearer understanding of the role of body weight/weight gain/body fat in the development of breast cancer and more importantly a clarification of potential mechanism(s) of action will provide valuable insights into prevention strategies.

Estrogen and Body Weight

For postmenopausal women significant increases in estrone, estradiol, and free estradiol are associated with increasing BMI (45,46,47,48,49,50,51). This relationship may be modified by physical activity resulting in lower serum levels of estrogens from higher levels of activity (47). If not considered during data analysis, this could impact interpretation of results about estrogen’s relationship to body weight. Data on whether alcohol intake affects serum estrogens in postmenopausal women are not consistent. Some studies indicate that increased intake is associated with higher serum estrogens, whereas others do not indicate this response (47,48,50). Estradiol levels have been similar in premenopausal obese and lean women (52).

Body Fat as the Source of Estrogen

The biosynthesis of estrogens differs between premenopausal and postmenopausal women (53). Premenopausal women mainly synthesize estrogens in the ovary. However, in postmenopausal women ovarian biosynthesis is replaced by peripheral site synthesis, and in obese postmenopausal women, adipose tissue is the main source of estrogen biosynthesis. The primary mediator of postmenopausal estrogen biosynthesis is aromatase, which is actually a complex of enzymes (54) that is found in adipose tissue in the breast as well as tumor tissue itself (55). Androgens produced by the adrenal cortex and the postmenopausal ovary are converted into estrogens by aromatase (56,57). This mechanism of estrogen production can lead to local estrogen levels in breast tumors that are as much as 10-fold higher compared with the circulation (58), although this is something that cannot routinely be measured. In addition, TNFα and IL-6 are both secreted by adipocytes and can act in either autocrine or paracrine manners to increase production of aromatase, which is directly related to increased synthesis of estrogen (59). A number of different aromatase inhibitors are currently used to control the peripheral production of estrogens in women who have had breast cancer, and additional applications for the aromatase inhibitors are being evaluated (55).

Estrogen and Breast Cancer

It was established over 15 yr ago that serum estrogen levels can account for differences in breast cancer risk, as reviewed in Ref. 60. However, because of the variable estrogen levels throughout the menstrual cycle, there are limited reports using data obtained from premenopausal women (61). Thus, the focus of the relationship between estrogens and breast cancer has been primarily on postmenopausal breast cancer. In the prospective Hormones and Diet in the Etiology of Breast Cancer study, there was no significant relationship of estrogen to postmenopausal breast cancer when evaluated by tertiles of estradiol levels; however, there was a significant mean difference when age-adjusted case vs. control analysis was performed (62). One metaanalysis of six prospective studies indicated that women that developed postmenopausal breast cancer had a significant approximate 15% increase of estrogens compared with those that did not develop the disease (63). A second more recent metaanalysis of nine prospective studies indicated a doubling of breast cancer risk for the highest serum estrogen levels (64). Results from the Nurses Health Study also support this relationship (65). Another study evaluating results from the Nurses Health Study indicated that postmenopausal breast cancer risk was increased in women with higher estrogen levels, particularly with respect to tumors that were classified as both estrogen receptor (ER) and progesterone receptor (PR) positive (66). A very recent update of the Nurses Health Study indicated that elevated serum estrogens were associated with the development of breast cancer, regardless of risk assessment by either the Gail or Rosner and Colditz models (67). In the European Prospective Investigation into Cancer and Nutrition study, postmenopausal women who developed breast cancer had significantly higher total and free estradiol levels than did controls in blood samples collected 3 yr before diagnosis (68). Further analysis by quintiles also showed increased risk in relationship to increasing serum estradiol levels. For an extensive review of factors that influence estrogen levels in postmenopausal women and that may impact breast cancer development, see Ref. 69.

Tumor Receptor Status

Expression and function of the ER, PR, and human epidermal growth factor receptor 2 (HER-2) appear to be linked in many breast cancers, and their expression alone or together has implications for antiestrogen therapy and breast cancer outcomes (70). There have been a number of studies to determine whether these receptors may be of particular importance for obese patients, and the results indicate a complex picture of interdependence between the receptors that may depend on premenopausal vs. postmenopausal status and tumor progression. There are two different forms of the ER (ERα and ERβ) (71). ERα is the receptor that is commonly reported when discussing whether a tumor is ER+ or ER− because activation of ERα leads to increased cell proliferation. ERβ also binds estrogens but is controlled by a separate gene, and its presence in breast cancer cells is associated with a favorable prognosis (72). In addition, the ratio of ERα to ERβ is higher in beast tumors in comparison to normal tissue or benign tumors (73,74). Obesity and/or adult weight gain has primarily been associated with ERα+ tumors (28). Postmenopausal women in particular who are obese have had breast cancer that is often ERα+ (75), thus supporting the connection of obesity with elevated circulating estrogens promoting tumor development.

The PR has two main forms (PR-A and PR-B) that are derived from a single gene through the activation of two different promoters (76). Most clinical assays recognize both forms of the PR and will be referred to as PR for the purposes of this discussion. Studies have shown that BMI is positively correlated with both ER+ and PR+ tumors in postmenopausal women (34,28). The amount of weight gained from age 18 (28) or 20 yr (78) has also been directly correlated with both ER+ and PR+ breast cancer, further implicating the ER and PR in the growth of breast cancer.

HER-2 is a growth factor receptor that plays a role in regulating cell proliferation and is associated with aggressive types of breast cancer. The combination of increasing levels of HER-2 and PR was directly correlated with BMI in postmenopausal women but inversely correlated in premenopausal women (79). In contrast, when HER-2 expression alone was assessed, it was inversely related to BMI in postmenopausal women (80). Expression of the ER and PR may be most important during early stages of tumor development, but not in later development. Evidence to support this concept is that large tumors are more likely to be ER− and PR− (34). In addition, patients who are lymph node positive, i.e. have more advanced disease, more often have ER− and PR− tumors (81). This illustrates the complex interplay between these receptors.

Estrogen and Weight Reduction

Weight loss through either caloric restriction or gastric bypass surgery has been shown to lead to a reduction in circulating estrogens, although the relationship of the amount of weight lost to reductions in serum estrogens was not always proportional. For example, calorie restriction resulting in intakes of 1200 kcal/d using the American Heart Association step 2 diet for an average of 13.9 months resulted in an average weight loss of 14.5 kg (−15.6% of initial body weight) for postmenopausal women, whereas serum estradiol was reduced from an initial average of 25.5 to 17.9 pg/ml (82). In another study, weight reduction of 4% was associated with an 18% decrease of estradiol. This was not significant in women 50–65 yr of age, but there was a significant increase in SHBG (83).

A study of women with a mean age of 43.9 yr who had undergone Roux-en-Y gastric bypass surgery found that an average weight loss of 38.5 kg was accompanied by a decrease in estradiol from 53.9–35.7 pg/ml as well as a decrease in estrone from 69.6–48.1 pg/ml (84). Younger women with a mean age of 34.7 yr who underwent vertical banded gastroplasty lost 59 kg (percentage of body weight was not reported) 12 months after the procedure, whereas their serum levels of estradiol decreased from 94.85–73.62 pg/ml over the same period (85). Because many breast tumors in postmenopausal women are dependent on estrogen for growth, it seems likely that weight loss and the concomitant reduction in estrogen levels should lead to a reduction in breast tumor growth. In fact, a recently published paper supports this indicating that the incidence of breast cancer was reduced by 85% after gastric bypass surgery (86).

Preclinical Studies

In agreement with human studies, an increased incidence of spontaneous and chemically induced mammary tumors has been reported for obese and overweight rodents (87,88,89,90,91,92). Additional studies have shown leanness to protect dogs from spontaneous mammary development (93), whereas overweight is associated with an increased canine mammary tumor incidence (94).

In more recent studies, the effect of body weight on the development of mammary tumors in several transgenic mouse strains has been determined. For example, dietary induced obesity was reported to be associated with shortened mammary tumor latency in transgenic mouse mammary tumor virus (MMTV)-TGF-α mice (95,96), but not in MMTV-neu mice (97). MMTV-TGF-α mice develop tumors later in life that are considered to be hormone responsive. In contrast, the MMTV-neu mice develop ER− tumors (98). These findings are consistent with human studies cited previously, suggesting that obesity is more likely to be associated with the development of ER+ and/or hormone-responsive breast cancers.

There are few reports of the direct effect of estrogen in relationship to obesity and mammary tumor development in preclinical models. There is one paper published in 1966 that reported that when ovariectomized C3H mice, a strain of mice with a high incidence of spontaneous mammary tumors, were made obese by gold thioglucose injections, they had a decreased incidence of spontaneous mammary tumors, i.e. 6%, compared with an incidence rate of 44% for intact obese mice (99). Interestingly, no tumors appeared in normal weight ovariectomized mice, which was interpreted that there was a direct effect of caloric intake or obesity per se independent of estrogen on mammary tumor development. More recently, we attempted to investigate affects of gold thioglucose-induced obesity on the development of tumors from ER+ T47-D human breast cancer cells in a xenograft model (100). This study produced surprising results because we found in the first experiment that estrogen supplementation in ovariectomized obese mice resulted in no tumors being detected. In a second study that included both estrogen-supplemented and placebo groups, 100% tumor incidence was found in the obese placebo group compared with 50% in the nonobese placebo group, whereas, again, there were no tumors in the obese mice supplemented with estrogen. Analyses of the tumors that formed indicated that neither ERα nor ERβ was detected. In another study we investigated the effects of dietary induced obesity on tumor development from ER+ MCF-7 vs. ER− MDA-MB-231 human breast cancer cells (101). As expected there was little effect of body weight on tumor growth from the ER− MDA-MB-231 cells. Unfortunately, overall growth of the MCF-7 cells was not very robust, and it was not possible to determine any effects of body weight on ER+ tumor development.

Obesity-Related Factors that May Interact with Estrogen to Impact Breast Cancer

Obesity is associated with a number of additional circulating factors that may work independently as well as in concert with estrogen to impact breast cancer development. Most of the supporting evidence for these interactions results from in vitro studies in relationship to the ER status of human breast cancer cell lines. For example, insulin and IGF-I have had various effects on estrogen signaling in breast cancer cell lines, as reviewed in Ref. 53. There is increasing evidence that leptin, an adipose tissue-derived protein, which is positively associated with BMI and body fat, has different effects on ER+ and ER− human breast cancer cell lines. ER+ MCF-7 and T47-D cells express high levels of the leptin receptor signaling isoform, ObRl/Rb, whereas the shorter forms are present in ER− MDA-MB-231 and MDA-MB-435 cell lines (102). In addition, leptin receptor and ERα are coexpressed in breast cancer cell lines. In ER+ T47-D breast cancer cells, leptin induced cellular transformation (anchorage-independent growth) that was not observed in normal breast epithelial cells (103). In this and other ER+ breast cancer cell lines, the addition of leptin increases cell proliferation (103,104,105,106,107). Of particular interest to the focus of this review, it has been found that leptin modulates estrogen synthesis and ERα activity by up-regulation of aromatase gene expression and aromatase activity in MCF-7 cells, leading to increased estrogen synthesis (108).

Another adipose tissue-derived protein is adiponectin, which is reported to be inversely related with body weight/body fat. Receptors for adiponectin, adiponectin receptor (AdipoR) 1 and AdipoR2, are expressed in both ER+ and ER− human breast cancer cell lines (109,110,111,112). A recent study from our laboratory has shown that MCF-7, MDA-MB-231, MDA-MB-361, T47-D, and SKBR3 cells not only express AdipoR1 and AdipoR2, but also adiponectin itself (112). Of further interest, addition of adiponectin to different human breast cancer cell lines inhibited proliferation (109,111,112,77). When comparisons of different human breast cancer cell lines were made, adiponectin inhibited the proliferation of the ER− SK-BR-3 breast cancer cell line at a higher concentration than it inhibited ER+ MCF-7 and T47-D breast cancer cell lines (112) (44). This suggests an estrogen and adiponectin interaction. Adiponectin may also enhance aspects of apoptosis signaling in breast cancer cells (111,112), although one study showed no role of apoptosis in the inhibitory effect of adiponectin on T47-D cell proliferation (109).

Conclusions

It is now well established that obesity is a risk factor for postmenopausal breast cancer, particularly the development of hormone-responsive tumors. Elevated circulating estrogen levels as well as local production of this hormone have been implicated as a primary growth factor in this relationship. In addition, adipokines directly synthesized in adipose tissue may influence mammary tumorigenesis by impacting both circulating and locally produced levels of these proteins. Continuing research will determine whether these factors work independently and/or in concert with each other. Prevention of adult-onset obesity should be a major public health goal to delay or prevent some kinds of breast cancer.

Footnotes

This work was supported by funding from The Breast Cancer Research Foundation (to M.P.C.), National Institutes of Health-National Cancer Institute 101858 (to M.P.C.), Susan B. Komen for the Cure (K081178) (to M.E.G.), and The Hormel Foundation.

Disclosure Summary: The authors have nothing to declare.

First Published Online April 16, 2009

Abbreviations: AdipoR, Adiponectin receptor; BMI, body mass index; ER, estrogen receptor; HER-2, human epidermal growth factor receptor 2; MMTV, mouse mammary tumor virus; PR, progesterone receptor.

References

  • Cleary MP, Maihle NJ 1997 The role of body mass index in the relative risk of developing premenopausal versus postmenopausal breast cancer. Proc Soc Exp Biol Med 216:28–43 [PubMed]
  • Trentham-Dietz A, Newcomb PA, Storer BE, Longnecker MP, Baron J, Greenberg ER, Willett WC 1997 Body size and risk of breast cancer. Am J Epidemiol 145:1011–1019 [PubMed]
  • Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, Hennekens CH, Rosner B, Speizer FE, Willett WC 1997 Dual effects of weight and weight gain on breast cancer risk. JAMA 278:1407–1411 [PubMed]
  • McTiernan A 2000 Association between energy balance and body mass index and risk of breast carcinoma in women from diverse racial and ethnic backgrounds in the U.S. Cancer 88(Suppl):1248–1255 [PubMed]
  • Wolk A, Gridley G, Svenssson M, Nyrén O, McLaughlin JK, Fraumeni JF, Adami HO 2001 A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control 12:13–21 [PubMed]
  • Morimoto LM, White E, Chen Z, Chlebowski RT, Hays J, Kuller L, Lopez AM, Manson J, Margolis KL, Muti PC, Stefanick ML, McTiernan A 2002 Obesity, body size, and risk of postmenopausal breast cancer: the Women’s Health Initiative (United States). Cancer Causes Control 13:741–751 [PubMed]
  • Leong NM, Mignone LI, Newcomb PA, Titus-Ernstoff L, Baron JA, Trentham-Dietz A, Stampfer MJ, Willett WC, Egan KM 2003 Early life risk factors in cancer: the relation of birth weight to adult obesity. Int J Cancer 103:789–791 [PubMed]
  • Carpenter CL, Ross RK, Paganini-Hill A, Bernstein L 2003 Effect of family history, obesity and exercise on breast cancer risk among postmenopausal women. Int J Cancer 106:96–102 [PubMed]
  • Carmichael AR, Bates T 2004 Obesity and breast cancer: a review of the literature. Breast 13:85–92 [PubMed]
  • Pan SY, Johnson KC, Ugnat AM, Wen SW, Mao Y, Canadian Cancer Registries Epidemiology Research Group 2004 Association of obesity and cancer risk in Canada. Am J Epidemiol 159:259–268 [PubMed]
  • Cold S, Hansen S, Overvad K, Rose C 1998 A woman’s build and the risk of breast cancer. Eur J Cancer 34:1163–1174 [PubMed]
  • Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, Stanczyk FZ, Stephenson Jr HE, Falk RT, Miller R, Schatzkin A, Allen DS, Fentiman IS, Key TJ, Wang DY, Dowsett M, Thomas HV, Hankinson SE, Toniolo P, Akhmedkhanov A, Koenig K, Shore RE, Zeleniuch-Jacquotte A, Berrino F, Muti P, Micheli A, Krogh V, Sieri S, Pala V, Venturelli E, Secreto G, Barrett-Connor E, Laughlin GA, Kabuto M, Akiba S, Stevens RG, Neriishi K, Land CE, Cauley JA, Kuller LH, Cummings SR, Helzlsouer KJ, Alberg AJ, Bush TL, Comstock GW, Gordon GB, Miller SR, Longcope C, Endogenous Hormones Breast Cancer Collaborative Group 2003 Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95:1218–1226 [PubMed]
  • Sweeney C, Blair CK, Anderson KE, Lazovich D, Folsom AR 2004 Risk factors for breast cancer in elderly women. Am J Epidemiol 160:868–875 [PubMed]
  • Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D 2007 Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ 335:1134 [PMC free article] [PubMed]
  • Pathak DR, Whittemore AS 1992 Combined effects of body size, parity, and menstrual events on breast cancer incidence in seven countries. Am J Epidemiol 135:153–168 [PubMed]
  • Peacock SL, White E, Daling JR, Voigt LF, Malone KE 1999 Relation between obesity and breast cancer in young women. Am J Epidemiol 149:339–346 [PubMed]
  • Weiderpass E, Braaten T, Magnusson C, Kumle M, Vainio H, Lund E, Adami HO 2004 A prospective study of body size in different periods of life and risk of premenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 13:1121–1127 [PubMed]
  • Barnes-Josiah D, Potter JD, Sellers TA, Himes JH 1995 Early body size and subsequent weight gain as predictors of breast cancer incidence (Iowa, United States). Cancer Causes Control 6:112–118 [PubMed]
  • Kumar NB, Lyman GH, Allen K, Cox CE, Schapira DV 1995 Timing of weight gain and breast cancer. Cancer 76:243–249 [PubMed]
  • Magnusson C, Baron J, Persson I, Wolk A, Bergström R, Trichopoulos D, Adami HO 1998 Body size in different periods of life and breast cancer risk in post-menopausal women. Int J Cancer 76:29–34 [PubMed]
  • Ballard-Barbash R 1994 Anthropometry and breast cancer. Body size—a moving target. Cancer 74:1090–1100 [PubMed]
  • Li CI, Stanford JL, Daling JR 2000 Anthropometric variables in relation to risk of breast cancer in middle-aged women. Int J Epidemiol 29:208–213 [PubMed]
  • Enger SM, Ross RK, Paganini-Hill A, Carpenter CL, Bernstein L 2000 Body size, physical activity, and breast cancer hormone receptor status: results from two case-control studies. Cancer Epidemiol Biomarkers Prev 9:681–687 [PubMed]
  • Trentham-Dietz A, Newcomb PA, Egan KM, Titus-Ernstoff L, Baron JA, Storer BE, Stampfer MJ, Willett WC 2000 Weight change and risk of postmenopausal breast cancer (United States). Cancer Causes Control 11:533–542 [PubMed]
  • Friedenreich CM, Courneya KS, Bryant HE 2002 Case-control study of anthropometric measures and breast cancer risk. Int J Cancer 99:445–452 [PubMed]
  • Feigelson HS, Jonas CR, Teras LR, Thun MJ, Calle EE 2004 Weight gain, body mass index, hormone replacement therapy, and postmenopausal breast cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev 13:220–224 [PubMed]
  • Slattery ML, Sweeney C, Edwards S, Herrick J, Baumgartner K, Wolff R, Murtaugh M, Baumgartner R, Giuliano A, Byers T 2007 Body size, weight change, fat distribution and breast cancer risk in Hispanic and non-Hispanic white women. Breast Cancer Res Treat 102:85–101 [PubMed]
  • Ahn J, Schatzkin A, Lacey Jr JA, Albanes D, Ballard-Barbash R, Adams KF, Kipnis V, Mouw T, Hollenbeck AR, Leitzmann MF 2008 Adiposity, adult weight change, and postmenopausal beast cancer risk. Arch Intern Med 167:2091–2100 [PubMed]
  • Santen RJ, Boyd NF, Chlebowski RT, Cummings S, Cuzik J, Dowsett M, Easton D, Forbes JF, Key T, Hankinson SE, Howell A, Ingle JN 2007 Critical assessment of new risk factors for breast cancer: considerations for development of an improved risk prediction model. Endocr Relat Cancer 14:169–187 [PubMed]
  • Lahmann PH, Lissner L, Gullberg B, Olsson H, Berglund G 2003 A prospective study of adiposity and postmenopausal breast cancer risk: the Malmö Diet and Breast Cancer Study. Int J Cancer 103:246–252 [PubMed]
  • Lovegrove JA 2002 Obesity, body fat distribution and breast cancer. Nutr Res Rev 15:389–412 [PubMed]
  • Stephenson GD, Rose DP 2003 Breast cancer and obesity: an update. Nutr Cancer 45:1–16 [PubMed]
  • Friedenreich CM 2001 Review of anthropometric factors and breast cancer risk. Eur J Cancer Prev 10:15–32 [PubMed]
  • Maehle BO, Tretli S, Skjaerven R, Thorsen T 2001 Premorbid body weight and its relations to primary tumour diameter in breast cancer patients: its dependence on estrogen and progesterone receptor status. Breast Cancer Res Treat 68:159–169 [PubMed]
  • Berclaz G, Li S, Price KN, Coates AS, Castiglione-Gertsch M, Rudenstam CM, Holmberg SB, Lindtner J, Erien D, Collins J, Snyder R, Thürlimann B, Fey MF, Mendiola C, Werner ID, Simoncini E, Crivellari D, Gelber RD, Goldhirsch A, International Breast Cancer Study Group 2004 Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience. Ann Oncol 15:875–884 [PubMed]
  • Cleveland RJ, Eng SM, Abrahamson PE, Britton JA, Teitelbaum SL, Neugut AI, Gammon MD 2007 Weight gain prior to diagnosis and survival from breast cancer. Cancer Epidemiol Biomarkers Prev 16:1803–1811 [PubMed]
  • Demirkan B, Alacacioglu A, Yilmaz U 2007 Relation of body mass index (BMI) to disease free (DFS) and distant disease free survivals (DDFS) among Turkish women with operable breast cancer. Jpn J Clin Oncol 37:256–265 [PubMed]
  • Feigelson HS, Patel AV, Teras LR, Gansler TS, Thun MJ, Calle EE 2006 Adult weight gain and histopathologic characteristics of breast cancer among postmenopausal women. Cancer 107:12–21 [PubMed]
  • Barnett JB 2003 The relationship between obesity and breast cancer risk and mortality. Nutr Rev 61:73–76 [PubMed]
  • Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ 2003 Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638 [PubMed]
  • Daling JR, Malone KE, Doody DR, Johnson LG, Gralow JR, Porter PL 2001 Relation of body mass index to tumor markers and survival among young women with invasive ductal breast carcinoma. Cancer 92:720–729 [PubMed]
  • Barnett GC, Shah M, Redman K, Easton DF, Ponder BA, Pharoah PDP 2008 Risk factors for the incidence of breast cancer: do they affect survival from the disease? J Clin Oncol 26:3310–3316 [PubMed]
  • Dal Maso L, Zucchetto A, Talamini R, Serraino D, Stocco CF, Vercelli M, Falcini F, Franceschi S 2008 Effect of obesity and other lifestyle factors on mortality in women with breast cancer. Int J Cancer 123:2188–2194 [PubMed]
  • Reeves KW, Faulkner K, Modugno F, Hillier TA, Bauer DC, Ensrud KE, Cauley JA 2007 Body mass index and mortality among older breast cancer survivors in the Study of Osteoporotic Fractures. Cancer Epidemiol Biomarkers Prev 16:1468–1473 [PubMed]
  • Lukanova A, Lundin E, Zeleniuch-Jacquotte A, Muti P, Mure A, Rinaldi S, Dossus L, Micheli A, Arslan A, Lenner P, Shore RE, Krogh V, Koenig KL, Riboli E, Berrino F, Hallmans G, Stattin P, Toniolo P, Kaaks R 2004 Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women. Eur J Endocrinol 150:161–171 [PubMed]
  • Madigan MP, Troisi R, Potischman N, Dorgan JF, Brinton LA, Hoover RN 1998 Serum hormone levels in relation to reproductive and lifestyle factors in postmenopausal women (United States). Cancer Causes Control 9:199–207 [PubMed]
  • McTiernan A, Wu L, Chen C, Chlebowski R, Mossavar-Rahmani Y, Modugno F, Perri MG, Stanczyk FZ, Van Horn L, Wang CY, Women’s Health Initiative Investigators 2006 Relation of BMI and physical activity to sex hormones in postmenopausal women. Obesity (Silver Spring) 14:1662–1677 [PubMed]
  • Hankinson SE, Willett WC, Manson JE, Hunter DJ, Colditz GA, Stampfer MJ, Longcope C, Speizer FE 1995 Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J Natl Cancer Inst 87:1297–1302 [PubMed]
  • Boyapati SM, Shu XO, Gao YT, Dai Q, Yu H, Cheng JR, Jin F, Zheng W 2004 Correlations of blood sex steroid hormones with body size, body fat distribution, and other known risk factors for breast cancer in post-menopausal Chinese women. Cancer Causes Control 15:305–311 [PubMed]
  • Cauley JA, Gutai JA, Kuller LH, LeDonne D, Powell JG 1989 The epidemiology of serum sex hormones in postmenopausal women. Am J Epidemiol 129:1120–1131 [PubMed]
  • Bezemer ID, Rinaldi S, Dossus L, Gils CH, Peeters PH, Noord PA, Bueno-de- Mesquita HB, Johnsen SP, Overvad K, Olsen A, Tjønneland A, Boeing H, Lahmann PH, Linseisen J, Nagel G, Allen N, Roddam A, Bingham S, Khaw KT, Kesse E, Téhard B, Clavel-Chapelon F, Agudo A, Ardanaz E, Quiros JR, Amiano P, Martínez-Garcia C, Tormo MJ, Pala V, Panico S, Vineis P, Palli D, Tumino R, Trichopoulou A, Baibas N, Zilis D, Hémon B, Norat T, Riboli E, Kaaks R 2005 C-peptide, IGF-I, sex-steroid hormones and adiposity: a cross-sectional study in healthy women with the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control 16:561–572 [PubMed]
  • Cento RM, Proto C, Spada RS, Napolitano V, Ciampelli M, Cucinelli F, Lanzone A 1999 Leptin levels in menopause: effect of estrogen replacement therapy. Horm Res 52:269–273 [PubMed]
  • Lorincz AM, Sukumar S 2006 Molecular links between obesity and breast cancer. Endocr Relat Cancer 13:279–292 [PubMed]
  • Simpson ER, Ackerman GE, Smith ME, Mendelson CR 1981 Estrogen formation in stromal cells of adipose tissue of women: induction by glucocorticosteroids. Proc Natl Acad Sci USA 78:5690–5694 [PMC free article] [PubMed]
  • Miller WR 2006 Aromatase and the breast: regulation and clinical aspects. Maturitas 54:335–341 [PubMed]
  • Judd HL, Judd GE, Lucas WE, Yen SS 1974 Endocrine function of the postmenopausal ovary: concentration of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab 39:1020–1024 [PubMed]
  • Baird DT, Uno A, Melby JC 1969 Adrenal secretion of androgens and oestrogens. J Endocrinol 45:135–136 [PubMed]
  • van Landeghem AA, Poortman J, Nabuurs M, Thijssen JH 1985 Endogenous concentration and subcellular distribution of androgens in normal and malignant human breast tissue. Cancer Res 45:2907–2912 [PubMed]
  • Purohit A, Newman SP, Reed MJ 2002 The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. Breast Cancer Res 4:65–69 [PMC free article] [PubMed]
  • Bernstein L, Ross RK 1993 Endogenous hormones and breast cancer risk. Epidemiol Rev 15:48–65 [PubMed]
  • Bernstein L 2002 Epidemiology of endocrine-related risk factors for breast cancer. J Mammary Gland Biol Neoplasia 7:3–15 [PubMed]
  • Berrino F, Muti P, Micheli A, Bolelli G, Krogh V, Sciajno R, Pisani P, Panico S, Secreto G 1996 Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst 88:291–296 [PubMed]
  • Thomas HV, Reeves GK, Key TJA 1997 Endogenous estrogen and postmenopausal breast cancer: a quantitative review. Cancer Causes Control 8:922–928 [PubMed]
  • The Endogenous Hormones and Breast Cancer Collaborative Group 2002 Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94:606–616 [PubMed]
  • Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, Barbieri RL, Speizer FE 1998 Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 90:1292–1299 [PubMed]
  • Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE 2004 Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst 96:1856–1865 [PubMed]
  • Eliassen AH, Missmer SA, Tworoger SS, Hankinson SE 2006 Endogenous steroid hormone concentrations and risk of breast cancer: does the association vary by a women’s predicted breast cancer risk? J Clin Oncol 24:1823–1830 [PubMed]
  • Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PHM, Biessy C, Dossus L, Lukanova A, Bingham S, Khaw KT, Allen NE, Bueno-de-Mesquita HB, van Gils CH, Goobbee D, Boeing H, Lahmann PH, Nagel G, Chang-Claude J, Clave-Chapelon F, Fournier A, Thiébaut A, González CA, Quirós JR, Tormo MJ, Ardanaz E, Amiano P, Krogh V, Palli D, Panico S, Tumino R, Vineis P, Trichopoulou A, Kalapothaki V, Trichopoulos D, Ferrari P, Norat T, Saracci R, Riboli E 2005 Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer 12:1071–1082 [PubMed]
  • Kendall A, Folkerd EJ, Dowsett M 2007 Influences on circulating oestrogens in postmenopausal women: relationship with breast cancer. J Steroid Biochem Mol Biol 103:99–109 [PubMed]
  • Conzen SD 2008 Minireview: nuclear receptors and breast cancer. Mol Endocrinol 22:2215–2228 [PMC free article] [PubMed]
  • Maeso Fortuny MC, Brito Díaz B, Cabrera de León A 2006 Leptin, estrogens and cancer. Mini Rev Med Chem 6:897–907 [PubMed]
  • Omoto Y, Kobayashi S, Inoue S, Ogawa S, Toyama T, Yamashita H, Muramatsu M, Gustafsson JA, Iwase H 2002 Evaluation of oestrogen receptor β wild-type and variant protein expression, and relationship with clinicopathological factors in breast cancer. Eur J Cancer 38:380–386 [PubMed]
  • Roger P, Sahla ME, Mäkelä S, Gustafsson JA, Baldet P, Rochefort H 2001 Decreased expression of estrogen receptor β protein in proliferative preinvasive mammary tumors. Cancer Res 61:2537–2541 [PubMed]
  • Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P 2004 Loss of ERβ expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer 11:537–551 [PMC free article] [PubMed]
  • Rose DP, Komninou D, Stephenson GD 2004 Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev 5:153–165 [PubMed]
  • Jeltsch JM, Krozowski Z, Quirin-Stricker C, Gronemeyer H, Simpson RJ, Garnier JM, Krust A, Jacob F, Chambon P 1986 Cloning of the chicken progesterone receptor. Proc Natl Acad Sci USA 83:5424–5428 [PMC free article] [PubMed]
  • Wang Y, Lam JB, Lam KS, Liu J, Lam MC, Hoo RL, Wu D, Cooper GJ, Xu A 2006 Adiponectin modulates the glycogen synthase kinase-3β/β-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res 66:11462–11470 [PubMed]
  • Han D, Nie J, Bonner MR, McCann SE, Muti P, Tevisan M, Ramiriz-Marrero FA, Vito D, Freudenheim JL 2006 Lifetime adult weight gain, central adiposity, and the risk of pre- and postmenopausal breast cancer in the Western New York exposures and breast cancer study. Int J Cancer 119:2931–2937 [PubMed]
  • Sherman ME, Rimm DL, Yang XR, Chatterjee N, Brinton LA, Lissowska J, Peplonska B, Szeszenia-Dabrowska N, Zatonksi W, Cartun R, Mandich D, Rymkiewicz G, Ligaj M, Lukaszek S, Kordek R, Kalaylioglu Z, Harigopal M, Charrett L, Falk RT, Richesson D, Anderson WF, Hewitt SM, García-Closas M 2007 Variation in breast cancer hormone receptor and HER2 levels by etiologic factors: a population-based analysis. Int J Cancer 121:1079–1085 [PubMed]
  • Van Mieghen T, Leunen K, Pochet N, De Moor B, De Smet F, Amant F, Berteloot P, Timmerman D, Vanden Bempt I, Drijkoningen R, Wildiers H, Paridaens R, Smeets A, Hendrickx W, Van Limbergen E, Christiaens MR, Vergote I, Neven P 2007 Body mass index and HER-2 overexpression in breast cancer patients over 50 years of age. Breast Cancer Res Treat 106:127–133 [PubMed]
  • Maehle BO, Tretli S, Thorsen T 2004 The associations of obesity, lymph node status and prognosis in breast cancer patients: dependence estrogen and progesterone receptor status. APMIS 112:349–357 [PubMed]
  • Tchernof A, Nolan A, Sites CK, Ades PA, Poehlman ET 2002 Weight loss reduces c-reactive protein levels in obese postmenopausal women. Circulation 105:564–569 [PubMed]
  • Berrino F, Bellati C, Secreto G, Camerini E, Pala V, Panico S, Allegro G, Kaaks R 2001 Reducing bioavailable sex hormones through a comprehensive change in diet: the diet and androgens (DIANA) randomized trial. Cancer Epidemiol Biomarkers Prev 10:25–33 [PubMed]
  • Riedt CS, Brolin RE, Sherrell RM, Field MP, Shapses SA 2006 True fractional calcium absorption is decreased after Roux-en-Y gastric bypass surgery. Obesity (Silver Spring) 14:1940–1948 [PMC free article] [PubMed]
  • Bastounis EA, Karayiannakis AJ, Syrigos K, Zbar A, Makri GG, Alexiou D 1998 Sex hormone changes in morbidly obese patients after vertical banded gastroplasty. Eur Surg Res 30:43–47 [PubMed]
  • Christou NV, Leiberman M, Sampalis F, Sampalis JS 2008 Bariatric surgery reduces cancer risk in morbidly obese patients. Surg Obes Relat Dis 4:691–695 [PubMed]
  • Waxler SH, Tabar P, Melcher LP 1953 Obesity and the time of appearance of spontaneous mammary carcinoma in C3H mice. Cancer Res 13:276–278 [PubMed]
  • Waxler SH 1960 Obesity and cancer susceptibility in mice. Am J Clin Nutr 8:760–766
  • Seilkop SK 1995 The effect of body weight on tumor incidence and carcinogenicity testing in B6C3F1 mice and F344 rats. Fundam Appl Toxicol 24:247–259 [PubMed]
  • Haseman JK, Bourbina J, Eustis SL 1994 Effect of individual housing and other experimental design factors on tumor incidence in B6C3F1 mice. Fundam Appl Toxicol 23:44–52 [PubMed]
  • Wolff GL, Kodell RL, Cameron AM, Medina D 1982 Accelerated appearance of chemically induced mammary carcinomas in obese yellow (Avy/A) (BALB/c Xvy) F1 hybrid mice. J Toxicol Environ Health 10:131–142 [PubMed]
  • Klurfeld DM, Lloyd LM, Welch CB, Davis MJ, Tulp OL, Kritchevsky D 1991 Reduction of enhanced mammary carcinogenesis in LA/N-cp (corpulent) rats by energy restriction. Proc Soc Exp Biol Med 196:381–384 [PubMed]
  • Sonnenschein EG, Glickman LT, Goldschmidt MH, McKee LJ 1991 Body conformation, diet, and risk of breast cancer in pet dogs: a case-control study. Am J Epidemiol 133:694–703 [PubMed]
  • Pérez Alenza D, Rutterman GR, Peña L, Beynen AC, Cuesta P 1998 Relation between habitual diet and canine mammary tumors in a case-control study. J Vet Intern Med 12:132–139 [PubMed]
  • Cleary MP, Grande JP, Maihle NJ 2004 Effect of high fat diet on body weight and mammary tumor latency in MMTV-TGF-α mice. Int J Obes Relat Metab Disord 28:956–962 [PubMed]
  • Dogan S, Hu X, Zhang Y, Maihle NJ, Grande JP, Cleary MP 2007 Effects of high-fat diet and/or body weight on mammary tumor leptin and apoptosis signaling pathways in MMTV-TGF-α mice. Breast Cancer Res 9:R91 [PMC free article] [PubMed]
  • Cleary MP, Grande JP, Juneja SC, Maihle NJ 2004 Diet-induced obesity and mammary tumor development in MMTV-neu female mice. Nutr Cancer 50:174–180 [PubMed]
  • Wu K, Zhang Y, Xu XC, Hill J, Celestino J, Kim HT, Mohsin SK, Hilsenbeck SG, Lamph WW, Bissonette R, Brown PH 2002 The retinoid X receptor-selective retinoid, LGD1069, prevents the development of estrogen receptor-negative mammary tumors in transgenic mice. Cancer Res 62:6376–6380 [PubMed]
  • Waxler SH, Leef MF 1966 Augmentation of mammary tumors in castrated obese C3H mice. Cancer Res 26:860–862 [PubMed]
  • Nkhata KJ, Ray A, Dogan S, Grande JP, Cleary MP 2009 Mammary tumor development from T47-D human breast cancer cells in obese ovariectomized mice with and without estradiol supplements. Breast Cancer Res Treat 114:71–83 [PubMed]
  • Ray A, Nkhata K, Grande JP, Cleary MP 2007 Diet-induced obesity and mammary tumor development in relation to estrogen receptor status. Cancer Lett 253:291–300 [PubMed]
  • Garofalo C, Sisci D, Surmacz E 2004 Leptin interferes with the effects of the antiestrogen ICI 182.780 in MCF-7 breast cancer cell lines. Clin Cancer Res 10:6466–6475 [PubMed]
  • Hu X, Juneja SC, Maihle NJ, Cleary MP 2002 Leptin—a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 94:1704–1711 [PubMed]
  • Dieudonne MN, Machinal-Quelin F, Serazin-Leroy V, Leneveu MC, Pecquery R, Giudicelli Y 2002 Leptin mediates a proliferative response in human MCF7 breast cancer cells. Biochem Biophys Res Commun 293:622–628 [PubMed]
  • Laud K, Gourdou I, Pessemesse L, Peyrat JP, Dijane J 2002 Identification of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line. Mol Cell Endocrinol 188:219–226 [PubMed]
  • Ray A, Nkhata KJ, Cleary MP 2007 Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status. Int J Oncol 30:1499–1509 [PubMed]
  • Frankenberry KA, Skinner H, Somasundar P, McFadden DW, Vona-Davis LC 2006 Leptin receptor expression and cell signaling in breast cancer. Int J Oncol 28:985–993 [PubMed]
  • Catalano S, Marsico S, Giordano C, Mauro L, Rizza P, Panno ML, Andò S 2003 Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J Biol Chem 278:28668–28676 [PubMed]
  • Körner A, Pazaitou-Panayiotou K, Kelesidis T, Kelesidis I, Williams CJ, Kaprara A, Bullen J, Neuwirth A, Tseleni S, Mitsiades N, Kiess W, Mantzoros CS 2007 Total and high-molecular-weight adiponectin in breast cancer: in vitro and in vivo studies. J Clin Endocrinol Metab 92:1041–1048 [PubMed]
  • Takahata C, Miyoshi Y, Irahara N, Taguchi T, Tamaki Y, Noguchi S 2007 Demonstration of adiponectin receptors 1 and 2 mRNA expression in human breast cancer cells. Cancer Lett 250:229–236 [PubMed]
  • Dieudonne MN, Bussiere M, Dos Santos E, Leneveu MC, Giudicelli Y, Pecquery R 2006 Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem Biophys Res Commun 345:271–279 [PubMed]
  • Grossmann ME, Nkhata KJ, Mizuno NK, Ray A, Cleary MP 2008 Effects of adiponectin on breast cancer cell growth and signaling. Br J Cancer 98:370–379 [PMC free article] [PubMed]

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