title: Association of high obesity with PAM50 breast cancer intrinsic subtypes and gene expression.
abstract: BACKGROUND
  Invasive breast cancers are now commonly classified using gene expression into biologically and clinically distinct tumor subtypes. However, the role of obesity in breast tumor gene expression and intrinsic subtype is unknown.
  
  
  METHODS
  Early-stage breast cancer (BC) patients (n = 1,676) were sampled from two prospective cohorts. The PAM50 qRT-PCR assay was used to: a) assess tumor gene expression levels for ESR1, PGR, ERBB2, and 10 proliferation genes and b) classify tumors into intrinsic subtype (Luminal A, Luminal B, Basal-like, HER2-enriched, Normal-like). Body mass index (BMI) around BC diagnosis (kg/m(2)) was categorized as: underweight (<18.5), normal (18.5-24), overweight (25-29), mildly obese (30-34), and highly obese (≥35). In a cross-sectional analysis, we evaluated associations of BMI with gene expression using linear regression models, and associations of BMI with non-Luminal A intrinsic subtypes, compared with Luminal A subtype, using multinomial logistic regression. Statistical significance tests were two-sided.
  
  
  RESULTS
  Highly obese women had tumors with higher expression of proliferation genes compared with normal weight women (adjusted mean difference = 0.44; 95% CI: 0.18, 0.71), yet mildly obese (adjusted mean difference = 0.16; 95% CI: -0.06, 0.38) and overweight (adjusted mean difference = 0.18; 95% CI: -0.01, 0.36) women did not. This association was stronger in postmenopausal women (p for interaction = 0.06). Being highly obese, however, was inversely associated with ESR1 expression (adjusted mean difference = -0.95; 95% CI: -1.47, -0.42) compared with being normal weight, whereas being mildly obese and overweight were not. In addition, women with Basal-like and Luminal B subtypes, relative to those with Luminal A subtype, were more likely to be highly obese, compared with normal-weight.
  
  
  CONCLUSIONS
  ER expression may not increase correspondingly with increasing degree of obesity. Highly obese patients are more likely to have tumor subtypes associated with high proliferation and poorer prognosis.
authors.affiliation: Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA. Marilyn.L.Kwan@kp.org.
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Kwan
authors.affiliation: Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA. Candyce.H.Kroenke@kp.org.
authors.forename: Candyce H
authors.initials: CH
authors.lastname: Kroenke
authors.affiliation: Department of Internal Medicine, Division of Epidemiology, University of Utah, Salt Lake City, UT, USA. Carol.Sweeney@hsc.utah.edu.|Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA. Carol.Sweeney@hsc.utah.edu.
authors.forename: Carol
authors.initials: C
authors.lastname: Sweeney
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA. Philip.Bernard@hci.utah.edu.|The Associated Regional and University Pathologist Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA. Philip.Bernard@hci.utah.edu.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Bernard
authors.affiliation: Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA. Erin.K.Weltzien@kp.org.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Weltzien
authors.affiliation: Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA. Adrienne.Castillo@kp.org.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Castillo
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA. Rachel.Factor@path.utah.edu.|The Associated Regional and University Pathologist Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA. Rachel.Factor@path.utah.edu.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Factor
authors.affiliation: Department of Internal Medicine, Division of Epidemiology, University of Utah, Salt Lake City, UT, USA. Kaylynn.Maxfield@hsc.utah.edu.
authors.forename: Kaylynn S
authors.initials: KS
authors.lastname: Maxfield
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA. Inge.Stijleman@hci.utah.edu.
authors.forename: Inge J
authors.initials: IJ
authors.lastname: Stijleman
authors.affiliation: Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA. Larry.Kushi@kp.org.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Kushi
authors.affiliation: Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA. Charles.Quesenberry@kp.org.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Quesenberry
authors.affiliation: Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA. Laurel.Habel@kp.org.
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Habel
authors.affiliation: Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA. Bette.Caan@kp.org.
authors.forename: Bette J
authors.initials: BJ
authors.lastname: Caan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D001943:Breast Neoplasms / Q000145:classification / Q000150:complications / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; C506487:ESR1 protein, human; C508053:ERBB2 protein, human