br Steroid biosynthesis br Steroid hormone
Steroid hormone metabolism in breast cancer
Conclusion Steroid hormones elicit their biological actions primarily by binding to steroid receptors such as the ER, AR, PR and GR. Although classical breast cancer diagnostic panels assess the expression of the ER and PR, as well as HER2, it has been shown that breast cancers also express the AR and GR (Buxant et al., 2010, Moinfar et al., 2003, Belova et al., 2009, Iacopetta et al., 2012). However, steroid hormones can be converted into many other steroids that may or may not bind the same steroid receptor as the precursor steroid, or may in fact bind to membrane receptors as shown for the progesterone metabolite, 5αP. This highlights the fact that current therapies targeting the suppression of hormone actions via steroid receptors may not be adequate. Moreover, some steroids may augment disease development or progression by activating more than one receptor or allow crosstalk between receptors, a topic that we do not elaborate on in this review. A greater understanding of how classical steroid receptors influence the activities of each other and membrane receptors will be important to fully understand treatment options in breast cancer subtypes. Much like is the case with the heterogeneous expression of steroid receptors in breast cancer, the expression of steroid metabolising Pioglitazone synthesis is also heterogeneous and the expression levels of the different enzymes and their individual substrate preferences can have a significant effect on the flux through the various steroid producing pathways. Steroid metabolism in breast cancer subtypes can therefore not all be painted with the same brush. It is thus important to obtain a better understanding of steroid hormone producing enzymes in breast carcinoma tissues, as the ratio of steroids and their metabolites promoting cancer versus those inhibiting cancer, will likely determine the status and/or progression of breast cancer tumours. To date, our understanding of the intracrinology of breast cancer has been limited by both the availability of sample material, as well as the assays used to measure steroids from the limited available samples. Individual studies have tended to focus on a select group of steroids representative of an individual pathway, without consideration of global steroid metabolism. In many cases the availability of analytical techniques has driven this selective approach, with many studies relying on immunoassays. Recent advances in mass spectrometry based assays have made it possible to measure multiple steroids simultaneously, however, challenges regarding the limits of quantification for selected steroids and standardisation between laboratories remain (Bloem et al., 2015, Keevil, 2016). Despite the advances in analytical technologies, researchers are still inclined to focus on individual pathways and thus assays for the comprehensive quantification of the steroid metabolome are still lacking. While it is possible to analyse the same sample with multiple methods, each analysing individual pathways, and thus including the majority of the steroid metabolome, this is not always feasible as the acquisition of adequate sample material remains a hurdle due the invasive nature of the procedures which require informed consent and are not part of standard treatments (Capper et al., 2016, Wu et al., 2013). Much work is therefore still required to understand the intricacies of steroid metabolism in breast cancer as well as the activity of the resulting metabolites.
Acknowledgements This work is based on the research supported in part by the National Research Foundation of South Africa (Grant Numbers 98886, and 99114) and the Medical Research Council of South Africa. We would like to express our gratitude to Renate Louw-du Toit and Meghan Perkins for the critical proofreading of the manuscript and Trish Storbeck for the preparation of the illustrations.