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Hormones and Cancer

, Volume 1, Issue 1, pp 34–43 | Cite as

Specific Overexpression of Cyclin E·CDK2 in Early Preinvasive and Primary Breast Tumors in Female ACI Rats Induced by Estrogen

  • S. John Weroha
  • Wilma L. Lingle
  • Yan Hong
  • Sara Antonia Li
  • Jonathan J. LiEmail author
Article

Abstract

Overexpressed Aurora A, amplified centrosomes, and aneuploidy are salient features of estrogen-induced mammary preinvasive lesions and tumors in female August–Copenhagen Irish (ACI) rats. Intimately involved in these events are cyclins and their associated cyclin-dependent kinase (CDK) partners. Cyclin E1·CDK2 overexpression plays an important dual role in late G1/S phase of the cell cycle in cancer cells. It increases DNA replication providing growth advantage to cancer cells and facilitates aberrant centrosome duplication, generating chromosomal instability and aneuploidy leading to tumor development. Presented herein, a 24.0- and 45.0-fold elevation in cyclin E1 and CDK2 was found in 17β-estradiol (E2)-induced ACI rat mammary tumors (MTs), respectively. Cyclin E·CDK2 positive staining was confined to the large round cells found within focal dysplasias, ductal carcinomas in situ, and invasive MTs. Co-immunoprecipitation and in vitro kinase activity of these tumors revealed that these cell cycle entities are functional. When mammary tissue derived from untreated normal, E2-induced hyperplasia and primary tumors were normalized to cyclin E1 levels, low molecular weight (LMW) cyclin E1 forms (33- and 45-kDa) were detected in all of these tissue groups. Moreover, increasing concentrations of protease inhibitor in tissue lysates resulted in a marked reduction of LMW forms, indicating that the presence of cyclin E1 LMW forms can be markedly reduced. Significant increases in cyclin E1 mRNA (2.1-fold) were detected in primary ACI rat E2-induced breast tumors, and quantitative real-time polymerase chain reaction revealed a 20% amplification of the cyclin E1 gene (CCNE1). Collectively, these results support the involvement of cyclin E1·CDK2 in centrosome overduplication during each stage of E2-induced mammary tumorigenesis.

Keywords

Cyclin E1·CDK2 Estrogen ACI rat Breast cancer 

Abbreviations

BC

Breast cancer

CCNE1

Cyclin E1 gene

CDK

Cyclin-dependent kinase

DCIS

Ductal carcinoma in situ

E2

17β-estradiol

ERα

Estrogen receptor α

LMW

Low molecular weight

MT

Mammary tumor

PR

Progesterone receptor

SE

Standard error

Notes

Acknowlegements

The authors acknowledge the expert clerical assistance of Ms. Lauren Overton from the University of Kansas Medical Center, Department of Pharmacology.

Disclosures

None.

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Copyright information

© Springer 2010

Authors and Affiliations

  • S. John Weroha
    • 1
    • 2
    • 4
  • Wilma L. Lingle
    • 3
  • Yan Hong
    • 1
    • 2
  • Sara Antonia Li
    • 1
    • 2
  • Jonathan J. Li
    • 1
    • 2
    Email author
  1. 1.Hormonal Oncogenesis LaboratoryUniversity of Kansas Cancer CenterKansasUSA
  2. 2.Department of Pharmacology, Toxicology, and TherapeuticsUniversity of Kansas Medical CenterKansasUSA
  3. 3.The Tumor Biology Program, Division of Experimental PathologyMayo Clinic and FoundationRochesterUSA
  4. 4.Mayo Graduate School, Mayo Clinic and FoundationRochesterUSA

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