More than 3,000 women die of breast cancer each year in Australia. While hormonal and targeted treatments have shown benefit, metastatic disease is incurable. New targets and new approaches are clearly needed for this disease. We have discovered a number of small molecule compounds (ANI-7, NAP-6, 10-Cl-BBQ, 11-Cl-BBQ) that are nano-molar potent and up to 5000-fold more selective at killing breast cancer cells grown in culture than in cells from other tumour types or normal breast cells. We have shown these compounds to induce DNA damage after bioactivation by the Aryl hydrocarbon Receptor (AhR) pathway involving monooxygenase (CYP1, phase I) metabolic conversion.
Traditionally, the AhR pathway is known to metabolise environmental toxins via ligand induced translocation of AhR to the nucleus where it stimulates the expression of drug metabolising enzymes by binding to the xenobiotic response elements in their promotor regions. The primary metabolising enzymes are the CYP1 family that hydroxylate aryl compounds. These phase I enzymes also work in concert with phase II metabolising enzymes including, sulfotransferases (SULT1A1) to inactivate and solubilise compounds for excretion, as is the case with estrogen and the anti-estrogenic compound, tamoxifen. However, dependent upon the initial chemical composition this process of hydroxylation and subsequent sulfation can also produce highly reactive intermediates that bind DNA and induce cell death, as is the case with our group of compounds.
We now show that SULT1A1, phase II metabolism is indeed an additional downstream metabolic component to the activation and biological activity of our compounds. Moreover, inhibition of CYP1 and SULT1A1 enzymatic function ameliorates the effect of these compounds in cell line models of breast cancer. Furthermore, we present data to show that endogenous expression of AhR and SULT1A1 predicts for drug sensitivity in our panel of cell lines, while endogenous CYP1 activity does not.
We also show that AhR and SULT1A1 is highly expressed in breast cancer tissue including ER+, HER2, and TN (Triple Negative receptor) from 20 breast cancer patients compared with matched normal breast tissue obtained from the Hunter Cancer Biobank, NSW, Australia and stained for AhR and SULT1A1 expression using IHC methodology.
This study highlights the vulnerability of breast cancer to this type of approach, moreover, the inherent overexpression of these drug metabolising pathways may well shed light on the role of environmental toxins and harmful hydrocarbons on the induction of this cancer type.