Breast Cancer Research and Treatment

, Volume 137, Issue 1, pp 237–246 | Cite as

Hypothesized role of pregnancy hormones on HER2+ breast tumor development

  • Giovanna I. Cruz
  • María Elena Martínez
  • Loki Natarajan
  • Betsy C. Wertheim
  • Manuela Gago-Dominguez
  • Melissa Bondy
  • Adrian Daneri-Navarro
  • María Mercedes Meza-Montenegro
  • Luis Enrique Gutierrez-Millan
  • Abenaa Brewster
  • Pepper Schedin
  • Ian K. Komenaka
  • J. Esteban Castelao
  • Angel Carracedo
  • Carmen M. Redondo
  • Patricia A. Thompson


Breast cancer incidence rates have declined among older but not younger women; the latter are more likely to be diagnosed with breast cancers carrying a poor prognosis. Epidemiological evidence supports an increase in breast cancer incidence following pregnancy with risk elevated as much as 10 years post-partum. We investigated the association between years since last full-term pregnancy at the time of diagnosis (≤10 or >10 years) and breast tumor subtype in a case series of premenopausal Hispanic women (n = 627). Participants were recruited in the United States, Mexico, and Spain. Cases with known estrogen receptor (ER), progesterone receptor (PR), and HER2 status, with one or more full-term pregnancies ≥1 year prior to diagnosis were eligible for this analysis. Cases were classified into three tumor subtypes according to hormone receptor (HR+ = ER+ and/or PR+; HR− = ER− and PR−) expression and HER2 status: HR+/HER2−, HER2+ (regardless of HR), and triple negative breast cancer. Case-only odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated for HER2+ tumors in reference to HR+/HER2− tumors. Participants were pooled in a mixed-effects logistic regression model with years since pregnancy as a fixed effect and study site as a random effect. When compared to HR+/HER2− cases, women with HER2+ tumors were more likely be diagnosed in the post-partum period of ≤10 years (OR = 1.68; 95 % CI, 1.12–2.52). The effect was present across all source populations and independent of the HR status of the HER2+ tumor. Adjusting for age at diagnosis (≤45 or >45 years) did not materially alter our results (OR = 1.78; 95 % CI, 1.08–2.93). These findings support the novel hypothesis that factors associated with the post-partum breast, possibly hormonal, are involved in the development of HER2+ tumors.


Breast cancer Breast tumor subtypes Etiologic heterogeneity HER2 Hispanic Parity 



This study was supported by a grant from the National Cancer Institute (UO1CA153086); a Susan G. Komen for the Cure® Post-baccalaureate Training in Disparities Research Grant (KG090934); the Avon Foundation; a supplement to the Arizona Cancer Center Core Grant from the National Cancer Institute (CA-023074-2953); a supplement to the M.D. Anderson Cancer Center SPORE in Breast Cancer (P50 CA116199-02S1); FIS Intrasalud (PS09/02368); Programa Grupos Emergentes EMER ISCIII, Instituto de Salud Carlos III, Servicio Galego Saúde (SERGAS), Oncology and Genetics Unit. Complejo Hospitalario Universitario de Vigo, Spain; and the Botin Foundation. We are indebted to Ana Lilia Amador, Leticia Cordova, Carole Kepler, and Fang Wang for their contribution.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Giovanna I. Cruz
    • 1
  • María Elena Martínez
    • 2
  • Loki Natarajan
    • 2
  • Betsy C. Wertheim
    • 3
  • Manuela Gago-Dominguez
    • 4
  • Melissa Bondy
    • 5
  • Adrian Daneri-Navarro
    • 6
  • María Mercedes Meza-Montenegro
    • 7
  • Luis Enrique Gutierrez-Millan
    • 8
  • Abenaa Brewster
    • 9
  • Pepper Schedin
    • 10
  • Ian K. Komenaka
    • 11
  • J. Esteban Castelao
    • 12
  • Angel Carracedo
    • 4
  • Carmen M. Redondo
    • 12
  • Patricia A. Thompson
    • 13
  1. 1.School of Public HealthUniversity of California, BerkeleyBerkeleyUSA
  2. 2.Moores UCSD Cancer CenterUniversity of California, San Diego La JollaUSA
  3. 3.Arizona Cancer CenterUniversity of ArizonaTucsonUSA
  4. 4.Genomic Medicine Group, Galician Foundation of Genomic MedicineComplejo Hospitalario Universitario de Santiago, SERGAS, IDISSantiago de CompostelaSpain
  5. 5.Department of PediatricsDan L. Duncan Cancer Center, Baylor College of MedicineHoustonUSA
  6. 6.Universidad de GuadalajaraGuadalajaraMexico
  7. 7.Instituto Tecnológico de SonoraCiudad ObregonMexico
  8. 8.Universidad de SonoraHermosilloMexico
  9. 9.Department of Clinical Cancer PreventionM.D. Anderson Cancer Center, University of TexasHoustonUSA
  10. 10.Department of Medicine, Division of Medical OncologyUniversity of Colorado Anschutz Medical CampusDenverUSA
  11. 11.Department of SurgeryMaricopa Medical CenterPhoenixUSA
  12. 12.Oncology and Genetics Unit, Genomic Medicine Group, SERGASComplejo Hospitalario Universitario de VigoVigoSpain
  13. 13.Department of Cellular and Molecular MedicineCollege of Medicine, University of ArizonaTucsonUSA

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