Activation of the estrogen-signaling pathway by p21(WAF1/CIP1) in estrogen receptor-negative breast cancer cells

Xiaomei Chen, Christopher Danes, Michael Lowe, Thaddeus W. Herliczek, Khandan Keyomarsi

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Background: Estrogen stimulates the proliferation of cells in normal mammary glands and most estrogen receptor (ER)-positive mammary carcinomas by binding to the ER and promoting the transcription of ER-responsive genes. In cells with functional ERs, estrogen mediates the transition of cells from the G1 to S phase of the cell cycle. Several cell cycle regulatory proteins have been implicated in the ER-signaling pathway involved in estrogen-mediated growth stimulation and antiestrogen-mediated growth arrest. We sought to determine whether p21, a cyclin-dependent kinase inhibitor, is a component of this pathway and, if so, whether it can mediate estrogen's action in ER-negative breast cancer cells. Methods: We overexpressed p21 with a tetracycline-inducible system in ER-negative, p21-negative breast cancer cells. Activity of the ER-signaling pathway was monitored in transient transfection assays by using constructs in which the ER promoter or the estrogen-response element (ERE) controls Luciferase expression. The growth-modulating effects of estradiol and antiestrogens on p21-overexpressing clones were assessed. All P values are from two-sided tests. Results: A strong positive association was found between the expression of p21 and ER in nine breast cancer cell lines and in tumor samples from 60 patients with breast cancer (P<.001). Overexpression of p21 in a p21-negative, ER-negative cell line induced both the ER and ERE promoters in an estrogen-responsive manner. Last, stable p21 clones that also lack the expression of wild-type ER were responsive to the growth-inhibitory effects of ICI 182,780, a potent antiestrogen, and the growth-stimulatory effects of 17β-estradiol. Conclusion: The ability of p21 to mediate the activation of the estrogen-signaling pathway in ER-negative tumor cells suggests that p21 plays a novel role in this pathway, a finding that also has important clinical implications.

Original languageEnglish (US)
Pages (from-to)1403-1413
Number of pages11
JournalJournal of the National Cancer Institute
Volume92
Issue number17
StatePublished - Sep 6 2000

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Estrogen Receptors
Estrogens
Breast Neoplasms
Estrogen Receptor Modulators
Growth
Response Elements
Estradiol
Clone Cells
Cyclin-Dependent Kinase Inhibitor p21
Cell Cycle Proteins
Human Mammary Glands
Tetracycline
Tumor Cell Line
Luciferases
S Phase
Transfection
Cell Cycle
Cell Proliferation
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Activation of the estrogen-signaling pathway by p21(WAF1/CIP1) in estrogen receptor-negative breast cancer cells. / Chen, Xiaomei; Danes, Christopher; Lowe, Michael; Herliczek, Thaddeus W.; Keyomarsi, Khandan.

In: Journal of the National Cancer Institute, Vol. 92, No. 17, 06.09.2000, p. 1403-1413.

Research output: Contribution to journalArticle

Chen, Xiaomei ; Danes, Christopher ; Lowe, Michael ; Herliczek, Thaddeus W. ; Keyomarsi, Khandan. / Activation of the estrogen-signaling pathway by p21(WAF1/CIP1) in estrogen receptor-negative breast cancer cells. In: Journal of the National Cancer Institute. 2000 ; Vol. 92, No. 17. pp. 1403-1413.
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AU - Herliczek, Thaddeus W.

AU - Keyomarsi, Khandan

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N2 - Background: Estrogen stimulates the proliferation of cells in normal mammary glands and most estrogen receptor (ER)-positive mammary carcinomas by binding to the ER and promoting the transcription of ER-responsive genes. In cells with functional ERs, estrogen mediates the transition of cells from the G1 to S phase of the cell cycle. Several cell cycle regulatory proteins have been implicated in the ER-signaling pathway involved in estrogen-mediated growth stimulation and antiestrogen-mediated growth arrest. We sought to determine whether p21, a cyclin-dependent kinase inhibitor, is a component of this pathway and, if so, whether it can mediate estrogen's action in ER-negative breast cancer cells. Methods: We overexpressed p21 with a tetracycline-inducible system in ER-negative, p21-negative breast cancer cells. Activity of the ER-signaling pathway was monitored in transient transfection assays by using constructs in which the ER promoter or the estrogen-response element (ERE) controls Luciferase expression. The growth-modulating effects of estradiol and antiestrogens on p21-overexpressing clones were assessed. All P values are from two-sided tests. Results: A strong positive association was found between the expression of p21 and ER in nine breast cancer cell lines and in tumor samples from 60 patients with breast cancer (P<.001). Overexpression of p21 in a p21-negative, ER-negative cell line induced both the ER and ERE promoters in an estrogen-responsive manner. Last, stable p21 clones that also lack the expression of wild-type ER were responsive to the growth-inhibitory effects of ICI 182,780, a potent antiestrogen, and the growth-stimulatory effects of 17β-estradiol. Conclusion: The ability of p21 to mediate the activation of the estrogen-signaling pathway in ER-negative tumor cells suggests that p21 plays a novel role in this pathway, a finding that also has important clinical implications.

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