Skip to main content

Advertisement

SpringerLink
Log in

Hypothesized role of pregnancy hormones on HER2+ breast tumor development

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Brinton LA, Sherman ME, Carreon JD, Anderson WF (2008) Recent trends in breast cancer among younger women in the United States. J Natl Cancer Inst 100(22):1643–1648. doi:10.1093/jnci/djn344

    Article  PubMed  Google Scholar 

  2. DeSantis C, Howlader N, Cronin KA, Jemal A (2011) A Breast cancer incidence rates in U.S. women are no longer declining. Cancer Epidemiol Biomarkers Prev 20(5):733–739. doi:10.1158/1055-9965.EPI-11-0061

    Article  PubMed  Google Scholar 

  3. Martinez ME, Nielson CM, Nagle R, Lopez AM, Kim C, Thompson P (2007) Breast cancer among Hispanic and non-Hispanic White women in Arizona. J Health Care Poor Underserved 18(4 Suppl):130–145. doi:10.1353/hpu.2007.0112

    Article  PubMed  Google Scholar 

  4. Elledge RM, Clark GM, Chamness GC, Osborne CK (1994) Tumor biologic factors and breast cancer prognosis among white, Hispanic, and black women in the United States. J Natl Cancer Inst 86(9):705–712

    Article  PubMed  CAS  Google Scholar 

  5. Hedeen AN, White E (2001) Breast cancer size and stage in Hispanic American women, by birthplace: 1992–1995. Am J Public Health 91(1):122–125

    Article  PubMed  CAS  Google Scholar 

  6. Rodriguez-Cuevas S, Macias CG, Franceschi D, Labastida S (2001) Breast carcinoma presents a decade earlier in Mexican women than in women in the United States or European countries. Cancer 91(4):863–868. doi:10.1002/1097-0142(20010215)91:4<863:AID-CNCR1074>3.0.CO;2-Y

    Article  PubMed  CAS  Google Scholar 

  7. Li CI, Malone KE, Daling JR (2003) Differences in breast cancer stage, treatment, and survival by race and ethnicity. Arch Intern Med 163(1):49–56

    Article  PubMed  Google Scholar 

  8. Sorlie T (2004) Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Eur J Cancer 40(18):2667–2675. doi:10.1016/j.ejca.2004.08.021

    Article  PubMed  CAS  Google Scholar 

  9. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093

    Article  PubMed  CAS  Google Scholar 

  10. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874. doi:10.1073/pnas.19136709898/19/10869

    Article  PubMed  CAS  Google Scholar 

  11. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502. doi:10.1001/jama.295.21.2492

    Article  PubMed  CAS  Google Scholar 

  12. Trivers KF, Lund MJ, Porter PL, Liff JM, Flagg EW, Coates RJ, Eley JW (2009) The epidemiology of triple-negative breast cancer, including race. Cancer Causes Control 20(7):1071–1082. doi:10.1007/s10552-009-9331-1

    Article  PubMed  Google Scholar 

  13. Parise CA, Bauer KR, Brown MM, Caggiano V (2009) Breast cancer subtypes as defined by the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) among women with invasive breast cancer in California, 1999–2004. Breast J 15(6):593–602. doi:10.1111/j.1524-4741.2009.00822.x

    Article  PubMed  Google Scholar 

  14. Millikan RC, Newman B, Tse CK, Moorman PG, Conway K, Dressler LG, Smith LV, Labbok MH, Geradts J, Bensen JT, Jackson S, Nyante S, Livasy C, Carey L, Earp HS, Perou CM (2008) Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 109(1):123–139. doi:10.1007/s10549-007-9632-6

    Article  PubMed  Google Scholar 

  15. Martinez ME, Cruz GI, Brewster AM, Bondy ML, Thompson PA (2010) What can we learn about disease etiology from case–case analyses? Lessons from breast cancer. Cancer Epidemiol Biomarkers Prev 19(11):2710–2714. doi:10.1158/1055-9965.EPI-10-0742

    Article  PubMed  Google Scholar 

  16. Althuis MD, Fergenbaum JH, Garcia-Closas M, Brinton LA, Madigan MP, Sherman ME (2004) Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. Cancer Epidemiol Biomarkers Prev 13(10):1558–1568

    PubMed  CAS  Google Scholar 

  17. Clavel-Chapelon F (2002) Differential effects of reproductive factors on the risk of pre- and postmenopausal breast cancer. Results from a large cohort of French women. Br J Cancer 86(5):723–727. doi:10.1038/sj.bjc.6600124

    Article  PubMed  CAS  Google Scholar 

  18. Palmer JR, Wise LA, Horton NJ, Adams-Campbell LL, Rosenberg L (2003) Dual effect of parity on breast cancer risk in African–American women. J Natl Cancer Inst 95(6):478–483

    Article  PubMed  Google Scholar 

  19. Pathak DR, Osuch JR, He J (2000) Breast carcinoma etiology: current knowledge and new insights into the effects of reproductive and hormonal risk factors in black and white populations. Cancer 88(5 Suppl):1230–1238. doi:10.1002/(SICI)1097-0142(20000301)88:5+<1230:AID-CNCR9>3.0.CO;2-F

    Article  PubMed  CAS  Google Scholar 

  20. Albrektsen G, Heuch I, Kvale G (1995) The short-term and long-term effect of a pregnancy on breast cancer risk: a prospective study of 802,457 parous Norwegian women. Br J Cancer 72(2):480–484

    Article  PubMed  CAS  Google Scholar 

  21. Albrektsen G, Heuch I, Hansen S, Kvale G (2005) Breast cancer risk by age at birth, time since birth and time intervals between births: exploring interaction effects. Br J Cancer 92(1):167–175. doi:10.1038/sj.bjc.6602302

    Article  PubMed  CAS  Google Scholar 

  22. Liu Q, Wuu J, Lambe M, Hsieh SF, Ekbom A, Hsieh CC (2002) Transient increase in breast cancer risk after giving birth: postpartum period with the highest risk (Sweden). Cancer Causes Control 13(4):299–305

    Article  PubMed  Google Scholar 

  23. Lethaby AE, O’Neill MA, Mason BH, Holdaway IM, Harvey VJ (1996) Overall survival from breast cancer in women pregnant or lactating at or after diagnosis. Auckland Breast Cancer Study Group. Int J Cancer 67(6):751–755. doi:10.1002/(SICI)1097-0215(19960917)67:6<751:AID-IJC1>3.0.CO;2-Q

    Article  PubMed  CAS  Google Scholar 

  24. Kroman N, Mouridsen HT (2003) Prognostic influence of pregnancy before, around, and after diagnosis of breast cancer. Breast 12(6):516–521

    Article  PubMed  Google Scholar 

  25. Lyons TR, Schedin PJ, Borges VF (2009) Pregnancy and breast cancer: when they collide. J Mammary Gland Biol Neoplasia 14(2):87–98. doi:10.1007/s10911-009-9119-7

    Article  PubMed  Google Scholar 

  26. Borges VF, Schedin PJ (2012) Pregnancy-associated breast cancer: an entity needing refinement of the definition. Cancer 118(13):3226–3228. doi:10.1002/cncr.26643

    Article  PubMed  Google Scholar 

  27. Proietti CJ, Rosemblit C, Beguelin W, Rivas MA, Diaz Flaque MC, Charreau EH, Schillaci R, Elizalde PV (2009) Activation of Stat3 by heregulin/ErbB-2 through the co-option of progesterone receptor signaling drives breast cancer growth. Mol Cell Biol 29(5):1249–1265. doi:10.1128/MCB.00853-08

    Article  PubMed  CAS  Google Scholar 

  28. Richer JK, Lange CA, Manning NG, Owen G, Powell R, Horwitz KB (1998) Convergence of progesterone with growth factor and cytokine signaling in breast cancer. Progesterone receptors regulate signal transducers and activators of transcription expression and activity. J Biol Chem 273(47):31317–31326

    Article  PubMed  CAS  Google Scholar 

  29. Liu B, Ordonez-Ercan D, Fan Z, Huang X, Edgerton SM, Yang X, Thor AD (2009) Estrogenic promotion of ErbB2 tyrosine kinase activity in mammary tumor cells requires activation of ErbB3 signaling. Mol Cancer Res 7(11):1882–1892. doi:10.1158/1541-7786.mcr-08-0509

    PubMed  CAS  Google Scholar 

  30. Kwan ML, Kushi LH, Weltzien E, Maring B, Kutner SE, Fulton RS, Lee MM, Ambrosone CB, Caan BJ (2009) Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors. Breast Cancer Res 11(3):R31. doi:10.1186/bcr2261

    Article  PubMed  Google Scholar 

  31. Thompson PA, Brewster AM, Kim-Anh D, Baladandayuthapani V, Broom BM, Edgerton ME, Hahn KM, Murray JL, Sahin A, Tsavachidis S, Wang Y, Zhang L, Hortobagyi GN, Mills GB, Bondy ML (2011) Selective genomic copy number imbalances and probability of recurrence in early-stage breast cancer. PLoS ONE 6(8):e23543. doi:10.1371/journal.pone.0023543

    Article  PubMed  CAS  Google Scholar 

  32. Sutton P, Hamilton, BE, Mathews, TJ (2011) Recent decline in births in the United States, 2007–2009. NCHS Data Brief No. 60. National Center for Health Statistics, Hyattsville

  33. Martinez ME et al (2010) Comparative study of breast cancer in Mexican and Mexican–American women. Health 2(9):1040–1048. doi:10.4236/health.2010.29153

    Article  Google Scholar 

  34. Hammond MEH, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FCG, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC (2010) American Society of Clinical Oncology/College of American Pathologists Guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28(16):2784–2795. doi:10.1200/jco.2009.25.6529

    Article  PubMed  Google Scholar 

  35. Wolff AC, Hammond MEH, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF (2006) American Society of Clinical Oncology/College of American Pathologists Guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25(1):118–145. doi:10.1200/jco.2006.09.2775

    Article  PubMed  Google Scholar 

  36. Bladstrom A, Anderson H, Olsson H (2003) Worse survival in breast cancer among women with recent childbirth: results from a Swedish population-based register study. Clin Breast Cancer 4(4):280–285

    Article  PubMed  Google Scholar 

  37. Olson SH, Zauber AG, Tang J, Harlap S (1998) Relation of time since last birth and parity to survival of young women with breast cancer. Epidemiology 9(6):669–671

    Article  PubMed  CAS  Google Scholar 

  38. Hedges LV, Vevea JL (1998) Fixed- and random-effects models in meta-analysis. Psychol Methods 3(4):486–504

    Article  Google Scholar 

  39. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560. doi:10.1136/bmj.327.7414.557

    Article  PubMed  Google Scholar 

  40. Gaudet MM, Press MF, Haile RW, Lynch CF, Glaser SL, Schildkraut J, Gammon MD, Douglas Thompson W, Bernstein JL (2011) Risk factors by molecular subtypes of breast cancer across a population-based study of women 56 years or younger. Breast Cancer Res Treat 130(2):587–597. doi:10.1007/s10549-011-1616-x

    Article  PubMed  Google Scholar 

  41. Phipps AI, Malone KE, Porter PL, Daling JR, Li CI (2008) Reproductive and hormonal risk factors for postmenopausal luminal, HER-2-overexpressing, and triple-negative breast cancer. Cancer 113(7):1521–1526. doi:10.1002/cncr.23786

    Article  PubMed  Google Scholar 

  42. Xing P, Li J, Jin F (2010) A case-control study of reproductive factors associated with subtypes of breast cancer in Northeast China. Med Oncol 27(3):926–931. doi:10.1007/s12032-009-9308-7

    Article  PubMed  Google Scholar 

  43. Phipps AI, Buist DS, Malone KE, Barlow WE, Porter PL, Kerlikowske K, Li CI (2011) Reproductive history and risk of three breast cancer subtypes defined by three biomarkers. Cancer Causes Control 22(3):399–405. doi:10.1007/s10552-010-9709-0

    Article  PubMed  Google Scholar 

  44. Ma H, Wang Y, Sullivan-Halley J, Weiss L, Marchbanks PA, Spirtas R, Ursin G, Burkman RT, Simon MS, Malone KE, Strom BL, McDonald JA, Press MF, Bernstein L (2010) Use of four biomarkers to evaluate the risk of breast cancer subtypes in the women’s contraceptive and reproductive experiences study. Cancer Res 70(2):575–587. doi:10.1158/0008-5472.CAN-09-3460

    Article  PubMed  CAS  Google Scholar 

  45. Yang XR, Sherman ME, Rimm DL, Lissowska J, Brinton LA, Peplonska B, Hewitt SM, Anderson WF, Szeszenia-Dabrowska N, Bardin-Mikolajczak A, Zatonski W, Cartun R, Mandich D, Rymkiewicz G, Ligaj M, Lukaszek S, Kordek R, Garcia-Closas M (2007) Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev 16(3):439–443. doi:10.1158/1055-9965.EPI-06-0806

    Article  PubMed  CAS  Google Scholar 

  46. Tamimi RM, Colditz GA, Hazra A, Baer HJ, Hankinson SE, Rosner B, Marotti J, Connolly JL, Schnitt SJ, Collins LC (2012) Traditional breast cancer risk factors in relation to molecular subtypes of breast cancer. Breast Cancer Res Treat 131(1):159–167. doi:10.1007/s10549-011-1702-0

    Article  PubMed  CAS  Google Scholar 

  47. Daling JR, Malone KE, Doody DR, Anderson BO, Porter PL (2002) The relation of reproductive factors to mortality from breast cancer. Cancer Epidemiol Biomarkers Prev 11(3):235–241

    PubMed  Google Scholar 

  48. Pilewskie M, Gorodinsky P, Fought A, Hansen N, Bethke K, Jeruss J, Scholtens D, Khan SA (2012) Association between recency of last pregnancy and biologic subtype of breast cancer. Ann Surg Oncol 19(4):1167–1173. doi:10.1245/s10434-011-2104-6

    Article  PubMed  Google Scholar 

  49. Tamimi RM, Baer HJ, Marotti J, Galan M, Galaburda L, Fu Y, Deitz AC, Connolly JL, Schnitt SJ, Colditz GA, Collins LC (2008) Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancer. Breast Cancer Res 10(4):R67. doi:10.1186/bcr2128

    Article  PubMed  Google Scholar 

  50. Bhargava R, Dabbs DJ (2008) Luminal B breast tumors are not HER2 positive. Breast Cancer Res 10(5):404. doi:10.1186/bcr2134 author reply 405

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. School of Public Health, University of California, Berkeley, Berkeley, CA, USA

    Giovanna I. Cruz

  2. Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA, USA

    María Elena Martínez & Loki Natarajan

  3. Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

    Betsy C. Wertheim

  4. Genomic Medicine Group, Galician Foundation of Genomic Medicine, Complejo Hospitalario Universitario de Santiago, SERGAS, IDIS, Santiago de Compostela, Spain

    Manuela Gago-Dominguez & Angel Carracedo

  5. Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Melissa Bondy

  6. Universidad de Guadalajara, Guadalajara, Mexico

    Adrian Daneri-Navarro

  7. Instituto Tecnológico de Sonora, Ciudad Obregon, Mexico

    María Mercedes Meza-Montenegro

  8. Universidad de Sonora, Hermosillo, Mexico

    Luis Enrique Gutierrez-Millan

  9. Department of Clinical Cancer Prevention, M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA

    Abenaa Brewster

  10. Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Denver, CO, USA

    Pepper Schedin

  11. Department of Surgery, Maricopa Medical Center, Phoenix, AZ, USA

    Ian K. Komenaka

  12. Oncology and Genetics Unit, Genomic Medicine Group, SERGAS, Complejo Hospitalario Universitario de Vigo, Vigo, Spain

    J. Esteban Castelao & Carmen M. Redondo

  13. Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona, Arizona Cancer Center, 1515 N. Campbell Ave, P.O. Box 245024, Tucson, AZ, 85724, USA

    Patricia A. Thompson

Authors
  1. Giovanna I. Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. María Elena Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Loki Natarajan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Betsy C. Wertheim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manuela Gago-Dominguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Melissa Bondy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adrian Daneri-Navarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. María Mercedes Meza-Montenegro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Luis Enrique Gutierrez-Millan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Abenaa Brewster
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Pepper Schedin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ian K. Komenaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J. Esteban Castelao
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Angel Carracedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Carmen M. Redondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Patricia A. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patricia A. Thompson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cruz, G.I., Martínez, M.E., Natarajan, L. et al. Hypothesized role of pregnancy hormones on HER2+ breast tumor development. Breast Cancer Res Treat 137, 237–246 (2013). https://doi.org/10.1007/s10549-012-2313-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-012-2313-0

Keywords

Search

Navigation