The Role of Aryl Hydrocarbon Receptor and cross talk with Estrogen Receptor in Response of Breast Cancer to Novel Antitumor Agents Benzothiazoles and Aminoflavone

CALLERO, MARIANA; ANDREA IRENE LOAIZA PÉREZ

International Journal of Breast Cancer

SAGE-Hindawi Access to Research

Año: 2011

2090-3189

More treatments are needed for breast cancer patients who have stopped responding to hormonal therapies. Many estrogen receptor ER-expressing breast cancers become refractory to ER-based therapies. New antitumor drugs like AF and benzothiazoles 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 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 controled by the AhR-ARNT basic helix-loop-helix 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 predominatly nuclear AhR expression such as MDA-MB 231, are resistant. Thus, these drugs, unlike other neoplastic agents, require AhR-mediated signalling to cause DNA damage. This is a new treatment strategy for breast cancers with intact AhR signalling.