Breast Cancer Research and Treatment

, Volume 133, Issue 2, pp 617–634 | Cite as

Life stage differences in mammary gland gene expression profile in non-human primates

  • Petra Stute
  • Sonja Sielker
  • Charles E. Wood
  • Thomas C. Register
  • Cynthia J. Lees
  • Fitriya N. Dewi
  • J. Koudy Williams
  • Janice D. Wagner
  • Ulrich Stefenelli
  • J. Mark Cline
Preclinical study


Breast cancer (BC) is the most common malignancy of women in the developed world. To better understand its pathogenesis, knowledge of normal breast development is crucial, as BC is the result of disregulation of physiologic processes. The aim of this study was to investigate the impact of reproductive life stages on the transcriptional profile of the mammary gland in a primate model. Comparative transcriptomic analyses were carried out using breast tissues from 28 female cynomolgus macaques (Macaca fascicularis) at the following life stages: prepubertal (n = 5), adolescent (n = 4), adult luteal (n = 5), pregnant (n = 6), lactating (n = 3), and postmenopausal (n = 5). Mammary gland RNA was hybridized to Affymetrix GeneChip® Rhesus Macaque Genome Arrays. Differential gene expression was analyzed using ANOVA and cluster analysis. Hierarchical cluster analysis revealed distinct separation of life stage groups. More than 2,225 differentially expressed mRNAs were identified. Gene families or pathways that changed across life stages included those related to estrogen and androgen (ESR1, PGR, TFF1, GREB1, AR, 17HSDB2, 17HSDB7, STS, HSD11B1, AKR1C4), prolactin (PRLR, ELF5, STAT5, CSN1S1), insulin-like growth factor signaling (IGF1, IGFBP1, IGFBP5), extracellular matrix (POSTN, TGFB1, COL5A2, COL12A1, FOXC1, LAMC1, PDGFRA, TGFB2), and differentiation (CD24, CD29, CD44, CD61, ALDH1, BRCA1, FOXA1, POSTN, DICER1, LIG4, KLF4, NOTCH2, RIF1, BMPR1A, TGFB2). Pregnancy and lactation displayed distinct patterns of gene expression. ESR1 and IGF1 were significantly higher in the adolescent compared to the adult animals, whereas differentiation pathways were overrepresented in adult animals and pregnancy-associated life stages. Few individual genes were distinctly different in postmenopausal animals. Our data demonstrate characteristic patterns of gene expression during breast development. Several of the pathways activated during pubertal development have been implicated in cancer development and metastasis, supporting the idea that other developmental markers may have application as biomarkers for BC.


Breast development Gene microarray Breast cancer Stem cell Estrogen Progesterone 



Aldo-keto reductase family 1, member C4


v-akt Murine thymoma viral oncogene homolog 1


Aldehyde dehydrogenase 1 family, member A1


Androgen receptor


Breast cancer


Bone morphogenetic protein receptor, type 1A


Breast cancer 1


Cyclase-associated protein

CD24, CD29, CD44, CD61

Cluster designation antigens 24, 29, 44, and 61


Centromeric protein A


Collagen, type XII, alpha-1


Collagen, type V, alpha-2


Casein alpha S1


Dicer 1, ribonuclease type III


E74-like factor 5


Estrogen receptor alpha (protein)


Estrogen receptor beta (protein)


Estrogen receptor alpha (gene)


Estrogen receptor beta (gene)


Forkhead box A1


Forkhead box C1


Glutamyl-tRNA amidotransferase subunit A binding protein 3


Growth hormone


Gene regulated by estrogen in breast cancer 1


Glutathione s-transferase mu 3


11-beta-hydroxysteroid dehydrogenase type 1


17-beta-hydroxysteroid dehydrogenase type 2


17-beta-hydroxysteroid dehydrogenase type 7


Insulin-like growth factor 1


Insulin-like growth factor–binding protein 1


Insulin-like growth factor–binding protein 5


IgG heavy-chain locus


Janus kinase 2


Kruppel-like factor 4


Laminin, gamma-1


DNA ligase IV


Leucine-rich repeat protein, neuronal, 3


Proliferation-related antigen Ki67


Never in mitosis gene a–related kinase 10


Notch gene homolog 2


Principal components analysis


Platelet-derived growth factor receptor, alpha


Peroxisomal D3,D2-enoyl-CoA isomerase


Progesterone receptor


Progesterone receptor B




Protein phosphatase, PP2C domain-containing, 1K


Prolactin receptor


Receptor activator of NF-kappa-B ligand


RAP1 interacting factor homolog


Small EDRK-rich factor 1A


Signal transducer and activator of transcription 5


Steroid sulfatase




Trefoil factor 1


Transforming growth factor, beta-1


Transforming growth factor, beta-2


Transforming growth factor, beta-3


Wingless-related MMTV integration site 5B



The authors are grateful for the technical support of Ms. Hermina Borgerink, Ms. Jean Gardin, Ms. Lisa O’Donnell, and Mr. Joseph Finley and also for the work of students Ms. Sara Dillon, Ms. Amelia Hubbard, and Mr. Russell O’Donnell. This study has been supported by the German Research Foundation Grants STU 469/2-1 and STU 469/3-1 (to PS), a German Society of Obstetrics and Gynecology Grant (to PS), and National Institutes of Health Grants R01 AT00639-06 (to JMC), RO3 AG18170 (to TCR), R01 R01AG017864 (to JKW), and P40 RR 021380 (to JDW).


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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Petra Stute
    • 1
  • Sonja Sielker
    • 2
  • Charles E. Wood
    • 3
  • Thomas C. Register
    • 3
  • Cynthia J. Lees
    • 3
  • Fitriya N. Dewi
    • 3
  • J. Koudy Williams
    • 3
  • Janice D. Wagner
    • 3
  • Ulrich Stefenelli
    • 4
  • J. Mark Cline
    • 3
  1. 1.Department of Gynecologic Endocrinology and Reproductive MedicineUniversity Women’s HospitalBerneSwitzerland
  2. 2.Arrows Biomedical Deutschland GmbHMunsterGermany
  3. 3.Department of Pathology/Section on Comparative MedicineWake Forest University School of MedicineWinston-SalemUSA
  4. 4.Services-In-StatisticsWürzburgGermany

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