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Grant Details

Grant Number: 5R01CA050385-30 Interpret this number
Primary Investigator: Willett, Walter
Organization: Harvard School Of Public Health
Project Title: Risk Factors for Breast Cancer in Younger Nurses
Fiscal Year: 2019
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Abstract

DESCRIPTION (provided by applicant): With the follow-up of 116,430 women enrolled in the Nurses' Health Study II now supported by a cooperative agreement (UM1CA176726), this competing renewal continues the scientific pursuit of modifiable determinants of breast cancer risk, especially those acting during the premenopausal years. In this unique cohort, exposure information has been collected at two-year intervals, beginning in 1989 when women were 25-42 years of age, with 93% cumulative follow-up. Our focus on younger women with 28 years of follow-up allows examination of early adult exposures and breast cancers diagnosed before and after menopause; through 2017 we expect 6,232 incident breast cancer cases. Our extensive biorepository, with blood and cheek samples, tumor tissue, and mammograms, allows us to thoroughly examine relationships between lifestyle factors, biomarkers, intermediate endpoints, and tumor expression. In this proposal, we aim to identify dietary and metabolic factors associated with breast cancer risk, and to examine the underlying mechanistic pathways by incorporating plasma metabolomic profiles and tumor subtypes. The metabolome, defined as the set of small molecule metabolites that are the final downstream products of the genome, but which is also strongly influenced by diet and other modifiable factors, is critical for growth and maintenance of cells, tissues and entire organisms. Measuring specific metabolites in plasma, we propose to examine branched chain amino acids (valine, leucine, isoleucine) as well as evaluate more broadly metabolomic signatures that may be important in breast carcinogenesis. Building on previous work identifying dietary factors associated with breast cancer and diabetes, we will examine how these influence breast cancer through their effect on the metabolome, including intake of branched chain amino acids, dietary breast cancer risk factors (alcohol, red meat, fruits, vegetables), and a dietary diabetes risk reduction score. We will interrogate the PI3K/Akt/mTOR signaling pathway that regulates cell growth, proliferation, invasion, and survival and is important in breast cancer. Mutations in the PIK3CA gene or loss of PTEN, events present in 50-75% of breast tumors, lead to constitutively active mTOR. Dietary and other modifiable risk factors that influence this pathway would be expected to be associated specifically with tumors that do not already have an activated PI3K pathway due to these genetic changes. To evaluate the possible role of these mechanisms, we will examine metabolomic, dietary, and lifestyle factors in relation to breast cancer risk, incorporating tumor PIK3CA mutations and loss of PTEN. For any significant associations we observe, we will examine breast density as a mediator between exposures and breast cancer. Our aims will substantially enhance our understanding of the role of dietary factors, the metabolome, and the PI3K pathway in the etiology of breast cancer. These aims will identify potential preventive strategies, including dietary changes, and new metabolic targets for risk prediction and chemoprevention.

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Publications

Association Of Prevalent Hypertension With 24-hour Urinary Excretion Of Calcium, Citrate, And Other Factors
Authors: Taylor,E.N. , Mount,D.B. , Forman,J.P. , Curhan,G.C. .
Source: American Journal Of Kidney Diseases : The Official Journal Of The National Kidney Foundation, 2006 May; 47(5), p. 780-9.
PMID: 16632016
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A Prospective Study Of Breast Size And Premenopausal Breast Cancer Incidence
Authors: Kusano,A.S. , Trichopoulos,D. , Terry,K.L. , Chen,W.Y. , Willett,W.C. , Michels,K.B. .
Source: International Journal Of Cancer. Journal International Du Cancer, 2006-04-15 00:00:00.0; 118(8), p. 2031-4.
PMID: 16284954
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Natural Hair Color And The Incidence Of Endometriosis
Authors: Missmer,S.A. , Spiegelman,D. , Hankinson,S.E. , Malspeis,S. , Barbieri,R.L. , Hunter,D.J. .
Source: Fertility And Sterility, 2006 Apr; 85(4), p. 866-70.
PMID: 16580366
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A Prospective Study Of Pregravid Physical Activity And Sedentary Behaviors In Relation To The Risk For Gestational Diabetes Mellitus
Authors: Zhang,C. , Solomon,C.G. , Manson,J.E. , Hu,F.B. .
Source: Archives Of Internal Medicine, 2006-03-13 00:00:00.0; 166(5), p. 543-8.
PMID: 16534041
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Urinary 6-sulfatoxymelatonin Levels And Their Correlations With Lifestyle Factors And Steroid Hormone Levels
Authors: Schernhammer E.S. , Kroenke C.H. , Dowsett M. , Folkerd E. , Hankinson S.E. .
Source: Journal Of Pineal Research, 2006 Mar; 40(2), p. 116-24.
PMID: 16441548
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Validation Of Adolescent Diet Recalled By Adults
Authors: Maruti,S.S. , Feskanich,D. , Rockett,H.R. , Colditz,G.A. , Sampson,L.A. , Willett,W.C. .
Source: Epidemiology (cambridge, Mass.), 2006 Mar; 17(2), p. 226-9.
PMID: 16477265
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Association Between Plasma Prolactin Concentrations And Risk Of Breast Cancer Among Predominately Premenopausal Women
Authors: Tworoger S.S. , Sluss P. , Hankinson S.E. .
Source: Cancer Research, 2006-02-15 00:00:00.0; 66(4), p. 2476-82.
PMID: 16489055
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Preschool diet and adult risk of breast cancer.
Authors: Michels K.B. , Rosner B.A. , Chumlea W.C. , Colditz G.A. , Willett W.C. .
Source: International Journal Of Cancer. Journal International Du Cancer, 2006-02-01 00:00:00.0; 118(3), p. 749-54.
PMID: 16094624
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Coffee, Caffeine, And Risk Of Type 2 Diabetes: A Prospective Cohort Study In Younger And Middle-aged U.s. Women
Authors: van Dam,R.M. , Willett,W.C. , Manson,J.E. , Hu,F.B. .
Source: Diabetes Care, 2006 Feb; 29(2), p. 398-403.
PMID: 16443894
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Risk Factors For Urinary Incontinence Among Middle-aged Women
Authors: Danforth,K.N. , Townsend,M.K. , Lifford,K. , Curhan,G.C. , Resnick,N.M. , Grodstein,F. .
Source: American Journal Of Obstetrics And Gynecology, 2006 Feb; 194(2), p. 339-45.
PMID: 16458626
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Early Life Factors And Incidence Of Proliferative Benign Breast Disease
Authors: Baer,H.J. , Schnitt,S.J. , Connolly,J.L. , Byrne,C. , Willett,W.C. , Rosner,B. , Colditz,G.A. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2005 Dec; 14(12), p. 2889-97.
PMID: 16365006
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Duration Of Lactation And Incidence Of Type 2 Diabetes
Authors: Stuebe,A.M. , Rich-Edwards,J.W. , Willett,W.C. , Manson,J.E. , Michels,K.B. .
Source: Jama : The Journal Of The American Medical Association, 2005-11-23 00:00:00.0; 294(20), p. 2601-10.
PMID: 16304074
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Habitual Caffeine Intake And The Risk Of Hypertension In Women
Authors: Winkelmayer,W.C. , Stampfer,M.J. , Willett,W.C. , Curhan,G.C. .
Source: Jama : The Journal Of The American Medical Association, 2005-11-09 00:00:00.0; 294(18), p. 2330-5.
PMID: 16278361
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Vitamin D Intake And Risk Of Incident Hypertension: Results From Three Large Prospective Cohort Studies
Authors: Forman,J.P. , Bischoff-Ferrari,H.A. , Willett,W.C. , Stampfer,M.J. , Curhan,G.C. .
Source: Hypertension, 2005 Oct; 46(4), p. 676-82.
PMID: 16144983
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Diabetes Mellitus And The Risk Of Nephrolithiasis
Authors: Taylor,E.N. , Stampfer,M.J. , Curhan,G.C. .
Source: Kidney International, 2005 Sep; 68(3), p. 1230-5.
PMID: 16105055
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Dietary Pattern, Inflammation, And Incidence Of Type 2 Diabetes In Women
Authors: Schulze,M.B. , Hoffmann,K. , Manson,J.E. , Willett,W.C. , Meigs,J.B. , Weikert,C. , Heidemann,C. , Colditz,G.A. , Hu,F.B. .
Source: The American Journal Of Clinical Nutrition, 2005 Sep; 82(3), p. 675-84; quiz 714-5.
PMID: 16155283
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Smoking And Other Lifestyle Factors And The Risk Of Graves' Hyperthyroidism
Authors: Holm,I.A. , Manson,J.E. , Michels,K.B. , Alexander,E.K. , Willett,W.C. , Utiger,R.D. .
Source: Archives Of Internal Medicine, 2005-07-25 00:00:00.0; 165(14), p. 1606-11.
PMID: 16043678
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Mathematical Models Of Ovarian Cancer Incidence
Authors: Rosner,B.A. , Colditz,G.A. , Webb,P.M. , Hankinson,S.E. .
Source: Epidemiology (cambridge, Mass.), 2005 Jul; 16(4), p. 508-15.
PMID: 15951669
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Calcium And Vitamin D Intake And Risk Of Incident Premenstrual Syndrome
Authors: Bertone-Johnson,E.R. , Hankinson,S.E. , Bendich,A. , Johnson,S.R. , Willett,W.C. , Manson,J.E. .
Source: Archives Of Internal Medicine, 2005-06-13 00:00:00.0; 165(11), p. 1246-52.
PMID: 15956003
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Menstrual Cycle Characteristics And Incidence Of Premenopausal Breast Cancer
Authors: Terry,K.L. , Willett,W.C. , Rich-Edwards,J.W. , Hunter,D.J. , Michels,K.B. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2005 Jun; 14(6), p. 1509-13.
PMID: 15941964
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Outcome Of Patients With Ductal Carcinoma In Situ Untreated After Diagnostic Biopsy: Results From The Nurses' Health Study
Authors: Collins,L.C. , Tamimi,R.M. , Baer,H.J. , Connolly,J.L. , Colditz,G.A. , Schnitt,S.J. .
Source: Cancer, 2005-05-01 00:00:00.0; 103(9), p. 1778-84.
PMID: 15770688
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Dietary Flavonols And Flavonol-rich Foods Intake And The Risk Of Breast Cancer
Authors: Adebamowo C.A. , Cho E. , Sampson L. , Katan M.B. , Spiegelman D. , Willett W.C. , Holmes M.D. .
Source: International Journal Of Cancer, 2005-04-20 00:00:00.0; 114(4), p. 628-33.
PMID: 15609322
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Fatty Acid Intake And Incident Nephrolithiasis
Authors: Taylor,E.N. , Stampfer,M.J. , Curhan,G.C. .
Source: American Journal Of Kidney Diseases : The Official Journal Of The National Kidney Foundation, 2005 Feb; 45(2), p. 267-74.
PMID: 15685503
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High School Dietary Dairy Intake And Teenage Acne
Authors: Adebamowo C.A. , Spiegelman D. , Danby F.W. , Frazier A.L. , Willett W.C. , Holmes M.D. .
Source: Journal Of The American Academy Of Dermatology, 2005 Feb; 52(2), p. 207-14.
PMID: 15692464
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Obesity, Weight Gain, And The Risk Of Kidney Stones
Authors: Taylor,E.N. , Stampfer,M.J. , Curhan,G.C. .
Source: Jama : The Journal Of The American Medical Association, 2005-01-26 00:00:00.0; 293(4), p. 455-62.
PMID: 15671430
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Folate Intake And The Risk Of Incident Hypertension Among Us Women
Authors: Forman,J.P. , Rimm,E.B. , Stampfer,M.J. , Curhan,G.C. .
Source: Jama : The Journal Of The American Medical Association, 2005-01-19 00:00:00.0; 293(3), p. 320-9.
PMID: 15657325
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Adult Recall Of Adolescent Diet: Reproducibility And Comparison With Maternal Reporting
Authors: Maruti,S.S. , Feskanich,D. , Colditz,G.A. , Frazier,A.L. , Sampson,L.A. , Michels,K.B. , Hunter,D.J. , Spiegelman,D. , Willett,W.C. .
Source: American Journal Of Epidemiology, 2005-01-01 00:00:00.0; 161(1), p. 89-97.
PMID: 15615919
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Body Fatness During Childhood And Adolescence And Incidence Of Breast Cancer In Premenopausal Women: A Prospective Cohort Study
Authors: Baer,H.J. , Colditz,G.A. , Rosner,B. , Michels,K.B. , Rich-Edwards,J.W. , Hunter,D.J. , Willett,W.C. .
Source: Breast Cancer Research : Bcr, 2005; 7(3), p. R314-25.
PMID: 15987426
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Benign Breast Disease, Recent Alcohol Consumption, And Risk Of Breast Cancer: A Nested Case-control Study
Authors: Tamimi,R.M. , Byrne,C. , Baer,H.J. , Rosner,B. , Schnitt,S.J. , Connolly,J.L. , Colditz,G.A. .
Source: Breast Cancer Research : Bcr, 2005; 7(4), p. R555-62.
PMID: 15987462
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In Utero Exposures And The Incidence Of Endometriosis
Authors: Missmer,S.A. , Hankinson,S.E. , Spiegelman,D. , Barbieri,R.L. , Michels,K.B. , Hunter,D.J. .
Source: Fertility And Sterility, 2004 Dec; 82(6), p. 1501-8.
PMID: 15589850
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Reproductive History And Endometriosis Among Premenopausal Women
Authors: Missmer,S.A. , Hankinson,S.E. , Spiegelman,D. , Barbieri,R.L. , Malspeis,S. , Willett,W.C. , Hunter,D.J. .
Source: Obstetrics And Gynecology, 2004 Nov; 104(5 Pt 1), p. 965-74.
PMID: 15516386
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Sexual Orientation, Health Risk Factors, And Physical Functioning In The Nurses' Health Study Ii
Authors: Case P. , Austin S.B. , Hunter D.J. , Manson J.E. , Malspeis S. , Willett W.C. , Spiegelman D. .
Source: Journal Of Women's Health (2002), 2004 Nov; 13(9), p. 1033-47.
PMID: 15665660
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Incidence Of Laparoscopically Confirmed Endometriosis By Demographic, Anthropometric, And Lifestyle Factors
Authors: Missmer,S.A. , Hankinson,S.E. , Spiegelman,D. , Barbieri,R.L. , Marshall,L.M. , Hunter,D.J. .
Source: American Journal Of Epidemiology, 2004-10-15 00:00:00.0; 160(8), p. 784-96.
PMID: 15466501
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Association Of Weight Change, Weight Control Practices, And Weight Cycling Among Women In The Nurses' Health Study Ii
Authors: Field,A.E. , Manson,J.E. , Taylor,C.B. , Willett,W.C. , Colditz,G.A. .
Source: International Journal Of Obesity And Related Metabolic Disorders : Journal Of The International Association For The Study Of Obesity, 2004 Sep; 28(9), p. 1134-42.
PMID: 15263922
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Alcohol Intake And 8-year Weight Gain In Women: A Prospective Study
Authors: Wannamethee,S.G. , Field,A.E. , Colditz,G.A. , Rimm,E.B. .
Source: Obesity Research, 2004 Sep; 12(9), p. 1386-96.
PMID: 15483203
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Sugar-sweetened Beverages, Weight Gain, And Incidence Of Type 2 Diabetes In Young And Middle-aged Women
Authors: Schulze,M.B. , Manson,J.E. , Ludwig,D.S. , Colditz,G.A. , Stampfer,M.J. , Willett,W.C. , Hu,F.B. .
Source: Jama : The Journal Of The American Medical Association, 2004-08-25 00:00:00.0; 292(8), p. 927-34.
PMID: 15328324
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Glycemic Index, Glycemic Load, And Dietary Fiber Intake And Incidence Of Type 2 Diabetes In Younger And Middle-aged Women
Authors: Schulze,M.B. , Liu,S. , Rimm,E.B. , Manson,J.E. , Willett,W.C. , Hu,F.B. .
Source: The American Journal Of Clinical Nutrition, 2004 Aug; 80(2), p. 348-56.
PMID: 15277155
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A Prospective Study Of Diet And Benign Breast Disease
Authors: Webb,P.M. , Byrne,C. , Schnitt,S.J. , Connolly,J.L. , Jacobs,T.W. , Baer,H.J. , Willett,W.C. , Colditz,G.A. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2004 Jul; 13(7), p. 1106-13.
PMID: 15247120
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Functional impact of breast cancer by age at diagnosis.
Authors: Kroenke C.H. , Rosner B. , Chen W.Y. , Kawachi I. , Colditz G.A. , Holmes M.D. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2004-05-15 00:00:00.0; 22(10), p. 1849-56.
PMID: 15143077
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Dietary Factors And The Risk Of Incident Kidney Stones In Younger Women: Nurses' Health Study Ii
Authors: Curhan,G.C. , Willett,W.C. , Knight,E.L. , Stampfer,M.J. .
Source: Archives Of Internal Medicine, 2004-04-26 00:00:00.0; 164(8), p. 885-91.
PMID: 15111375
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Dietary intake of trans fatty acids and systemic inflammation in women.
Authors: Mozaffarian D. , Pischon T. , Hankinson S.E. , Rifai N. , Joshipura K. , Willett W.C. , Rimm E.B. .
Source: The American Journal Of Clinical Nutrition, 2004 Apr; 79(4), p. 606-12.
PMID: 15051604
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Adolescent Diet And Risk Of Breast Cancer
Authors: Frazier,A.L. , Li,L. , Cho,E. , Willett,W.C. , Colditz,G.A. .
Source: Cancer Causes & Control : Ccc, 2004 Feb; 15(1), p. 73-82.
PMID: 14970737
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Weight Cycling And The Risk Of Developing Type 2 Diabetes Among Adult Women In The United States
Authors: Field,A.E. , Manson,J.E. , Laird,N. , Williamson,D.F. , Willett,W.C. , Colditz,G.A. .
Source: Obesity Research, 2004 Feb; 12(2), p. 267-74.
PMID: 14981219
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Vitamin D Intake And Incidence Of Multiple Sclerosis
Authors: Munger,K.L. , Zhang,S.M. , O'Reilly,E. , Hernán,M.A. , Olek,M.J. , Willett,W.C. , Ascherio,A. .
Source: Neurology, 2004-01-13 00:00:00.0; 62(1), p. 60-5.
PMID: 14718698
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Processed Meat Intake And Incidence Of Type 2 Diabetes In Younger And Middle-aged Women
Authors: Schulze,M.B. , Manson,J.E. , Willett,W.C. , Hu,F.B. .
Source: Diabetologia, 2003 Nov; 46(11), p. 1465-73.
PMID: 14576980
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Premenopausal Dietary Carbohydrate, Glycemic Index, Glycemic Load, And Fiber In Relation To Risk Of Breast Cancer
Authors: Cho,E. , Spiegelman,D. , Hunter,D.J. , Chen,W.Y. , Colditz,G.A. , Willett,W.C. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2003 Nov; 12(11 Pt 1), p. 1153-8.
PMID: 14652274
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Adolescent Diet And Incidence Of Proliferative Benign Breast Disease
Authors: Baer,H.J. , Schnitt,S.J. , Connolly,J.L. , Byrne,C. , Cho,E. , Willett,W.C. , Colditz,G.A. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2003 Nov; 12(11 Pt 1), p. 1159-67.
PMID: 14652275
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Premenopausal Intakes Of Vitamins A, C, And E, Folate, And Carotenoids, And Risk Of Breast Cancer
Authors: Cho,E. , Spiegelman,D. , Hunter,D.J. , Chen,W.Y. , Zhang,S.M. , Colditz,G.A. , Willett,W.C. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2003 Aug; 12(8), p. 713-20.
PMID: 12917201
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Premenopausal Fat Intake And Risk Of Breast Cancer
Authors: Cho,E. , Spiegelman,D. , Hunter,D.J. , Chen,W.Y. , Stampfer,M.J. , Colditz,G.A. , Willett,W.C. .
Source: Journal Of The National Cancer Institute, 2003-07-16 00:00:00.0; 95(14), p. 1079-85.
PMID: 12865454
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Alcohol Drinking Patterns And Risk Of Type 2 Diabetes Mellitus Among Younger Women
Authors: Wannamethee,S.G. , Camargo,C.A. , Manson,J.E. , Willett,W.C. , Rimm,E.B. .
Source: Archives Of Internal Medicine, 2003-06-09 00:00:00.0; 163(11), p. 1329-36.
PMID: 12796069
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