Inhibition of the phosphatidylinositol 3-kinase/Akt pathway improves response of long-term estrogen-deprived breast cancer xenografts to antiestrogens

Gauri Sabnis, Olga Goloubeva, Danijela Jelovac, Adam Schayowitz, Angela Brodie

Research output: Contribution to journalArticle

Abstract

Purpose: Aromatase inhibitors that block the synthesis of estrogen are proving to be superior to antiestrogens and may replace tamoxifen as first-line treatment for postmenopausal estrogen receptor (ER) - positive breast cancer patients. However, acquisition of resistance to all forms of treatments is inevitable and a major clinical concern. In this study, we have investigated the effects of long-term estrogen deprivation in the breast cancer xenograft model and whether sensitivity to antiestrogens can be restored in vivo. We also compared whether combining wortmannin with tamoxifen or fulvestrant inhibited tumor growth better than either drug alone. Experimental Design: Long-term estrogen-deprived aromatase-transfected human ER-positive breast cancer cells (UMB-1Ca) were grown as tumors in ovariectomized athymic nude mice. Twelve weeks after inoculation, when tumors reached 300 mm3, animals were grouped and injected with vehicle, Δ4A, letrozole, tamoxifen, fulvestrant, wortmannin, tamoxifen plus wortmannin, and wortmannin plus fulvestrant. Tumor volumes were measured weekly. Results: Tumors of UMB-1Ca cells grew equally well with and without androstenedione, indicating the ability of the cells to proliferate in the absence of estrogen. The combination of wortmannin with tamoxifen or fulvestrant inhibited tumor growth better than either drug alone. The combination of wortmannin plus fulvestrant was the most effective treatment that maintained tumor regression for a prolonged time. Conclusion: These results suggest that blocking both ER and growth factor receptor pathways could provide effective control over tumor growth of long-term estrogen-deprived human breast cancers.

Original languageEnglish (US)
Pages (from-to)2751-2757
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number9
DOIs
StatePublished - May 1 2007
Externally publishedYes

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Phosphatidylinositol 3-Kinase
Estrogen Receptor Modulators
Heterografts
Estrogens
Tamoxifen
Breast Neoplasms
Neoplasms
Estrogen Receptors
letrozole
Nude Mice
Growth
Aromatase Inhibitors
Aromatase
Growth Factor Receptors
Androstenedione
Tumor Burden
Pharmaceutical Preparations
wortmannin
Research Design
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Inhibition of the phosphatidylinositol 3-kinase/Akt pathway improves response of long-term estrogen-deprived breast cancer xenografts to antiestrogens. / Sabnis, Gauri; Goloubeva, Olga; Jelovac, Danijela; Schayowitz, Adam; Brodie, Angela.

In: Clinical Cancer Research, Vol. 13, No. 9, 01.05.2007, p. 2751-2757.

Research output: Contribution to journalArticle

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