Up is Down...Left is Right? What Next?

[Tom]

It appears that the release of surprising research findings this week is not over just yet. This one is gonna floor you!

http://www.oncolink.com/resources/ar...th=12&id=12596




Estrogen may induce apoptosis in breast cancer resistant to antihormone therapy

Reuters Health
Posting Date: December 6, 2005

Last Updated: 2005-12-06 16:00:36 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Physiologic concentrations of estradiol may provoke breast cancer regression when estrogen-receptor-positive tumors become resistant to therapy with aromatase inhibitors, new study findings suggest.

Dr. V. Craig Jordan, from Fox Chase Cancer Center in Philadelphia, and his associates compared the growth characteristics of wild-type estrogen receptor-positive human breast cancer cells (MCF-7 cells) and those of long-term estrogen-deprived MCF-7:5C cells resistant to estrogen withdrawal. They report their findings in the Journal of the National Cancer Institute for December 7th.

Estrogen treatment increased the growth of the wild-type MCF-7 cells in vitro, with maximum stimulation at 0.1 nanomolar concentration, whereas treatment with the estrogen receptor antagonist fulvestrant reduced their growth, with maximum inhibition at 1 micromolar.

In contrast, 1 nanomolar estradiol induced apoptosis of the MCF-7:5C cells. Fulvestrant continued to exert an inhibitory effect at 1 micromolar, but to a lesser extent than the estradiol.

Their experiments showed that estradiol-induced regression was mediated by activation of the mitochondrial apoptotic pathway, as evidenced by increased expression of proapoptotic Bcl-2 family proteins, disruption of mitochondrial membrane integrity, and facilitation of the translocation of cytochrome 3 from the mitochondria into the cytosol.

Estradiol treatment also caused activation of caspase 9 and caspase 7 and cleavage of PARP.

Based on these findings, the research team suggests, "the apoptotic potential of estradiol is directly related to its ability to alter the ratio between proapoptotic and antiapoptotic proteins in target cells."

When they injected MCF-7:5C cells into the mammary fat pads of athymic mice, measurable tumors were detected within 4 weeks. Subsequent treatment with postmenopausal doses of estradiol led to complete regression of the tumors by week 8.

TUNEL assay of tumor sections at day 5 showed that 49.9% of cells in the estradiol-treated MCF-7:5C tumors were apoptotic, compared with 0.7% of cells in the vehicle-treated tumors.

Fulvestrant caused growth arrest and tumor stasis, but not apoptosis.

Dr. Jordan's team proposes that "if and when resistance to aromatase inhibition occurs, a strategy of treatment with estrogen (either exogenous estrogen or the woman's endogenous estrogen) may be sufficient to kill the cancer and control disease progression."

Once the tumoricidal action of estrogen is complete, they add, any remaining tumor may again become responsive to antihormonal therapy.

J Natl Cancer Inst 2005;97:1746-1759.