New Therapy Involves “Zinc Fingers”

According to the National Cancer Institute, nearly 216,000 women in the U.S. will be diagnosed with breast cancer this year — more than 40,000 of them will die.

A major player in many cases of breast cancer is the estrogen receptor. Once bound by an estrogen compound, the estrogen receptor can activate certain genes involved in breast cancer progression. Current breast-cancer therapies designed to prevent the binding of estrogen compounds to the estrogen receptor have met with limited success.

In their award-winning ESTC paper, however, SAIC's Li Hua Wang and co-authors identify a way to block breast cancer growth at the receptor-DNA level — perhaps a big step in the effort to save lives of breast cancer patients.

This alternative approach focuses on disrupting the bond between the estrogen receptor and DNA (the blueprint of how we develop). Certain structural features of the estrogen receptor, known as zinc fingers, appear to stabilize the receptor-DNA complex. (Previous research suggests that electrophilic compounds may attack these zinc fingers, thereby destabilizing the estrogen receptor-DNA complex.)

Wang and co-authors used two electrophilic compounds (a disulfide benzamide called DIBA and a benzisothiazolone derivative known as BITA) to effectively block the estrogen receptor-mediated growth of breast cancer cells and the growth of human breast tumors implanted in mice. A high dose of DIBA reduced tumor mass to undetectable levels. The compounds also interfered with the activation of genes controlling cell cycle and programmed cell death.

Their findings show that DIBA has anticancer activity, in vitro and in vivo, in estrogen-mediated breast carcinoma. The results also demonstrate that DIBA inhibits breast cancer cell growth by selectively blocking estrogen receptor zinc finger function, without significantly affecting other nuclear receptors.

This research represents a new type of molecular intervention strategy born from the collaboration of molecular modeling studies, biochemistry, and molecular biology, reflective of the great advances in all fields.

Future research will focus on optimizing the selectivity and potency of these promising new lead compounds in the treatment of breast cancer and determining whether they complement existing antiestrogen therapy.

The paper by SAIC's Li Hua Wang, Xiaoyi Yang, Xiaohu Zhang, Weihua Xiao, and Kelly Mihalic, "Suppression of Breast Cancer by Chemical Modulation of Vulnerable Zinc Fingers in Estrogen Receptor," appeared in Nature Medicine.

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