Abstract
Abstract Many advances have been made in the diagnosis and treatment of breast cancer in recent years, but it still remains one of the leading causes of death in women. It is well known that the growth of breast cells is regulated by the interactions of different steroid hormones, in particular androgens and estrogens that are related due to their connected metabolic pathways. A number of novel inhibitors of steroidogenic enzymes have been developed that target pre-receptor events_those pertaining to the production, transport, and conversion of steroid ligands. Critical pre-receptor steps include the conversion of pregnenolone-like steroids into androgens, mediated largely by the 17α-hydroxylase/lyase (CYP17) enzyme complex, and the conversion of testosterone and androstenedione to estradiol and estrone, mediated by aromatase (CYP19). Both conversions are implicated in the emergence of tumor resistance and thus are targets for intervention. Androgen Receptor (AR) is the sex hormone receptor most frequently found in both primary and secondary breast tumors, which is indicitative of the importance of AR in regulating the growth of breast cancer cells. It is estimated that 90% of human genes undergo alternative splicing and AR is no exception. Alternative splicing of the AR could culminate in a receptor that is capable of translocation, or can bind DNA without ligand, leading current AR therapies to be less efficacious. Using TaqMan qRT-PCR we examined 213 female breast-cancer FFPET samples, 80 ER- PR- Her2- samples, 68 ER- PR- Her2+ samples, and 64 ER+ PR+ Her2- samples, as well as 8 breast-cancer cell lines for the presence of ESR1, CYP17, CYP19, full length AR and AR splice variants ARV1, ARV3/V7, ARV567, and Delta3AR. ARV3/V7 and Delta3AR were the most prevalent variants in the ER+ PR+ Her2- and ER- PR- Her2+ sample sets, with >85% of these samples showing expression of either or both of these variants. On the other hand, ARV1, ARV3/V7, and ARV567 were the most prevalent variants in the ER- PR- Her2- sample set, with >90% of these samples showing expression of one or a combination of these variants. Lower expression values of most of the AR variants were observed in higher grade ER+ PR+ Her2- and ER- PR- Her2+ samples as compared to the lower grade samples. CYP19 was highly prevalent in all sample sets with >75% of all samples showing expression, while CYP17 expression was observed in <30% of all the samples tested. Our findings show the relatively high expression of AR variants and CYP19 in breast cancer tissues, which may indicate their role in regulating the growth of these tumors. Hence increased expression of AR splice variants in breast cancer tumors may be an important biomarker of resistance and targets for AR related therapy. Citation Format: Gabriela Martinez, Dana Gaffney, Katherine Bell, Suso Platero, Deborah Ricci, Weimin Li, Jayaprakash D. Karkera. Identification of androgen receptor splice variants, ESR1, CYP17, and CYP19 in human breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3467. doi:10.1158/1538-7445.AM2013-3467
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