Abstract
Abstract Deregulation of cyclin A expression has been associated with prognosis and tamoxifen responsiveness in breast cancer. We have previously reported an overexpression of cyclin A in two antiprogestin-resistant tumors derived from a hormone-dependent mammary carcinoma induced by medroxyprogesterone acetate (MPA). MPA-induced tumors show high levels of estrogen (ER) and progesterone receptors (PR) and transit through different stages of hormone dependency. Taking into account that antiprogestin-sensitive tumors show higher levels of PR isoform A (PRA) than isoform B (PRB), and that the opposite ratio is observed in the antiprogestin-resistant tumors, we decided to examine the expression of cyclin A in other experimental models containing different PRA/PRB ratios. An increase in cyclin A expression was observed by Western blot (WB) in the acquired antiprogestin-resistant variant C7-2-HIR and in the constitutive resistant C7-HI tumor (1.7 fold and 1.5 fold, respectively) compared to the antiprogestin-responsive tumor C7-2-HI (p<0.05). The immunohistochemical analysis of paraffin sections of the tumors confirmed these findings, showing a higher percentage of cyclin A positive nuclei in the antiprogestin-resistant tumor C7-HI, versus the responsive tumor C7-2-HI (p<0.01), suggesting an association of cyclin A expression with endocrine resistance in the murine breast cancer model. Next we evaluated the expression of cyclin A in T47D human breast cancer cells that express both PR isoforms and in T47D-YA or T47D-YB cells that express either PRA or PRB, respectively. The WB analysis of the nuclear fraction of cell lysates showed an increase in cyclin A expression in the T47D-YB cells (1.5 fold), compared to T47D and T47D-YA cells (all the cells were serum starved; p<0.01). Immunofluorescence for cyclin A using cultured breast cancer cells revealed a higher percentage of cyclin A positive nuclei in T47D-YB cells compared to T47D cells (p<0.001) or T47D-YA (p<0.01), respectively. Similarly, T47D-YB xenografts showed an increase of cyclin A expression by WB (1.47 fold) compared to T47D and T47D-YA tumors (p<0.05). These results suggest an association between cyclin A expression, the PR isoform ratio, and antiprogestin resistance. Cyclin A may participate in the ligand independent activation of PR in the antiprogestin-resistant variants of these experimental models of breast cancer. Citation Format: Marina Ayre, Melina E. Bilinski, Britta M. Jacobsen, Claudia Lanari, Victoria T. Fabris. Increased cyclin A expression is associated with antiprogestin resistance and progesterone receptor isoforms ratio in experimental models of breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A43.
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