Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells

Carolyn M. Cover, S. Jean Hsieh, Erin J. Cram, Chibo Hong, Jacques E. Riby, Leonard F. Bjeldanes, Gary L. Firestone

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

The current options for treating breast cancer are limited to excision surgery, general chemotherapy, radiation therapy, and, in a minority of breast cancers that rely on estrogen for their growth, antiestrogen therapy. The naturally occurring chemical indole-3-carbinol (I3C), found in vegetables of the Brassica genus, is a promising anticancer agent that we have shown previously to induce a G1 cell cycle arrest of human breast cancer cell lines, independent of estrogen receptor signaling. Combinations of I3C and the antiestrogen tamoxifen cooperate to inhibit the growth of the estrogen- dependent human MCF-7 breast cancer cell line more effectively than either agent alone. This more stringent growth arrest was demonstrated by a decrease in adherent and anchorage-independent growth, reduced DNA synthesis, and a shift into the G1 phase of the cell cycle. A combination of I3C and tamoxifen also caused a more pronounced decrease in cyclin-dependent kinase (CDK) 2-specific enzymatic activity than either compound alone but had no effect on CDK2 protein expression. Importantly, treatment with I3C and tamoxifen ablated expression of the phosphorylated retinoblastoma protein (Rb), an endogenous substrate for the G1 CDKs, whereas either agent alone only partially inhibited endogenous Rb phosphorylation. Several lines of evidence suggest that I3C works through a mechanism distinct from tamoxifen. I3C failed to compete with estrogen for estrogen receptor binding, and it specifically down-regulated the expression of CDK6. These results demonstrate that I3C and tamoxifen work through different signal transduction pathways to suppress the growth of human breast cancer cells and may, therefore, represent a potential combinatorial therapy for estrogen-responsive breast cancer.

Original languageEnglish (US)
Pages (from-to)1244-1251
Number of pages8
JournalCancer Research
Volume59
Issue number6
StatePublished - Mar 15 1999
Externally publishedYes

Fingerprint

MCF-7 Cells
Tamoxifen
Cell Cycle Checkpoints
Breast Neoplasms
Estrogens
Cyclin-Dependent Kinase 2
Growth
Estrogen Receptor Modulators
Estrogen Receptors
G1 Phase Cell Cycle Checkpoints
Cell Line
Retinoblastoma Protein
Brassica
G1 Phase
indole-3-carbinol
Vegetables
Antineoplastic Agents
Signal Transduction
Cell Cycle
Radiotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cover, C. M., Hsieh, S. J., Cram, E. J., Hong, C., Riby, J. E., Bjeldanes, L. F., & Firestone, G. L. (1999). Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Research, 59(6), 1244-1251.

Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. / Cover, Carolyn M.; Hsieh, S. Jean; Cram, Erin J.; Hong, Chibo; Riby, Jacques E.; Bjeldanes, Leonard F.; Firestone, Gary L.

In: Cancer Research, Vol. 59, No. 6, 15.03.1999, p. 1244-1251.

Research output: Contribution to journalArticle

Cover, CM, Hsieh, SJ, Cram, EJ, Hong, C, Riby, JE, Bjeldanes, LF & Firestone, GL 1999, 'Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells', Cancer Research, vol. 59, no. 6, pp. 1244-1251.
Cover CM, Hsieh SJ, Cram EJ, Hong C, Riby JE, Bjeldanes LF et al. Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Research. 1999 Mar 15;59(6):1244-1251.
Cover, Carolyn M. ; Hsieh, S. Jean ; Cram, Erin J. ; Hong, Chibo ; Riby, Jacques E. ; Bjeldanes, Leonard F. ; Firestone, Gary L. / Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. In: Cancer Research. 1999 ; Vol. 59, No. 6. pp. 1244-1251.
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