The Role of Aryl Hydrocarbon Receptor and Crosstalk with Estrogen Receptor in Response of Breast Cancer Cells to the Novel Antitumor Agents Benzothiazoles and Aminoflavone

الملخص EN

Many estrogen-receptor- (ER-) expressing breast cancers become refractory to ER-based therapies.

New antitumor drugs like aminoflavone (AF) and benzothiazoles (Bzs) have been developed and have exquisite antitumor activity in ER+MCF-7 and T47D cells and in a MCF-7 nude mouse model.

ER(−) breast cancer cells like MDA-MB-231 are less susceptible.

We previously found in MCF-7 cells that these drugs activate the aryl hydrocarbon receptor (AhR) via translocation to the nucleus, induction of AhR-specific DNA binding activity, and expression of CYP1A1, whose transcription is controlled by the AhR-ARNT transcription factor.

CYP1A1 metabolizes AF and Bz to a species which directly or after further metabolism damages DNA.

In contrast an AhR-deficient variant of MCF-7 or cells with predominantly nuclear AhR expression, such as MDA-MB 231, are resistant.

Thus, these drugs, unlike other neoplastic agents, require AhR-mediated signaling to cause DNA damage.

This is a new treatment strategy for breast cancers with intact AhR signaling.