Project 452037

Breast cancer was diagnosed in 26,900 Canadian women in 2019, accounting for 25% of all cancer diagnosis in women. Breast cancer patients with estrogen receptor positive cancers are usually treated, often for 5-10 years, with an antiestrogen medication called tamoxifen. There remain significant gaps in our knowledge, particularly in terms of how certain types of estrogens and the active form of tamoxifen known as endoxifen are handled by proteins known as drug transporters. In this application, we will leverage new insights and emerging evidence generated by my research laboratory and clinic of direct relevance to tamoxifen therapy for breast cancer patients, and propose studies that will define the importance of drug transporters that shuttle drugs in or out of the cell, as a determinant of estrogen and endoxifen cellular uptake or efflux. We will focus on a class of drug uptake transporters known as Organic Anion Transporting Polypeptide (OATP) transporters which have been detected in breast cancer tissue as well as efflux transporters such as P-glycoprotein (ABCB1) and BCRP (ABCG2) which have been also detected in breast cancer, and can pump drugs from inside to outside the cell. We will study the impact of OATP transporters on the cellular uptake and retention of estrogens such as estrone sulfate and dehydroepiandrosterone sulfate. This is important in that endoxifen counteracts the effect of estrogens in cells so that cancer cells do not activate estrogen receptors. We propose to use gene expression methods to study the function of these transporters as well as measure the amount of such proteins on the cell membrane using a mass spectrometer, and then engineer breast cancer cell lines to reflect expression of these transporters seen in human breast cancer using CRISPR technology, and also test such cell lines in tumor bearing mice which are treated with endoxifen as well as carry out drug level measurement studies in patients who take tamoxifen.