Hormone induced chromosomal instability in p53-null mammary epithelium

Debananda Pati, Bassem R. Haddad, Albert Haegele, Henry Thompson, Frances S. Kittrell, Anne Shepard, Cristina Montagna, Nenggang Zhang, Gouqing Ge, Subhendu Kumar Otta, Maureen McCarthy, Robert L. Ullrich, Daniel Medina

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The absence of p53 function increases risk for spontaneous tumorigenesis in the mammary gland. Hormonal stimulation enhances tumor risk in p53-null mammary epithelial cells as well as the incidence of aneuploidy. Aneuploidy appears in normal p53-null mammary epithelial cells within 5 weeks of hormone stimulation. Experiments reported herein assessed a possible mechanism of hormone-induced aneuploidy. Hormones increased DNA synthesis equally between wild-type (WT) and p53-null mammary epithelial cells. There were two distinct responses in p53-null cells to hormone exposure. First, Western blot analysis demonstrated that the levels of two proteins involved in regulating sister chromatid separation and the spindle checkpoint, Mad2 and separase (ESPL1) were increased in null compared with WT cells. In contrast, the levels of securin and Rad21 proteins were not increased in hormone-stimulated p53-null compared with WT cells. ESPL1 RNA was also increased in p53-null mouse mammary cells in vivo by 18 h of hormone stimulation and in human breast MCF7 cells in monolayer culture by 8 h of hormone stimulation. Furthermore, both promoters contained p53 and steroid hormone response elements. Mad2 protein was increased as a consequence of the absence of p53 function. The increase in Mad2 protein was observed also at the cellular level by immunohistochemistry. Second, hormones increased gene amplication in the distal arm of chromosome 2, as shown by comparative genomic hybridization. These results support the hypothesis that hormone stimulation acts to increase aneuploidy by several mechanisms. First, by increasing mitogenesis in the absence of the p53 checkpoint in G2, hormones allow the accumulation of cells that have experienced chromosome missegregation. Second, the absolute rate of chromosome missegregation may be increased by alterations in the levels of two proteins, separase and Mad2, which are important for maintaining chromosomal segregation and the normal spindle checkpoint during mitosis.

Original languageEnglish (US)
Pages (from-to)5608-5616
Number of pages9
JournalCancer Research
Volume64
Issue number16
DOIs
StatePublished - Aug 15 2004
Externally publishedYes

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Chromosomal Instability
Breast
Epithelium
Hormones
Mad2 Proteins
Aneuploidy
Separase
Epithelial Cells
Securin
Chromosomes
Null Lymphocytes
Chromatids
Comparative Genomic Hybridization
Chromosomes, Human, Pair 2
MCF-7 Cells
Response Elements
Human Mammary Glands
Mitosis
Carcinogenesis
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pati, D., Haddad, B. R., Haegele, A., Thompson, H., Kittrell, F. S., Shepard, A., ... Medina, D. (2004). Hormone induced chromosomal instability in p53-null mammary epithelium. Cancer Research, 64(16), 5608-5616. https://doi.org/10.1158/0008-5472.CAN-03-0629

Hormone induced chromosomal instability in p53-null mammary epithelium. / Pati, Debananda; Haddad, Bassem R.; Haegele, Albert; Thompson, Henry; Kittrell, Frances S.; Shepard, Anne; Montagna, Cristina; Zhang, Nenggang; Ge, Gouqing; Otta, Subhendu Kumar; McCarthy, Maureen; Ullrich, Robert L.; Medina, Daniel.

In: Cancer Research, Vol. 64, No. 16, 15.08.2004, p. 5608-5616.

Research output: Contribution to journalArticle

Pati, D, Haddad, BR, Haegele, A, Thompson, H, Kittrell, FS, Shepard, A, Montagna, C, Zhang, N, Ge, G, Otta, SK, McCarthy, M, Ullrich, RL & Medina, D 2004, 'Hormone induced chromosomal instability in p53-null mammary epithelium', Cancer Research, vol. 64, no. 16, pp. 5608-5616. https://doi.org/10.1158/0008-5472.CAN-03-0629
Pati D, Haddad BR, Haegele A, Thompson H, Kittrell FS, Shepard A et al. Hormone induced chromosomal instability in p53-null mammary epithelium. Cancer Research. 2004 Aug 15;64(16):5608-5616. https://doi.org/10.1158/0008-5472.CAN-03-0629
Pati, Debananda ; Haddad, Bassem R. ; Haegele, Albert ; Thompson, Henry ; Kittrell, Frances S. ; Shepard, Anne ; Montagna, Cristina ; Zhang, Nenggang ; Ge, Gouqing ; Otta, Subhendu Kumar ; McCarthy, Maureen ; Ullrich, Robert L. ; Medina, Daniel. / Hormone induced chromosomal instability in p53-null mammary epithelium. In: Cancer Research. 2004 ; Vol. 64, No. 16. pp. 5608-5616.
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