Editorial: Steroid hormone receptors and cell cycle in breast cancer

Centrosome amplification leads to aberrant mitosis, giving rise to aneuploidy and it has been associated with poor prognosis in human cancers. The aim of this study was to evaluate the relationship between polyploidy, centrosome abnormalities and response to endocrine treatment in progestin-induced mouse mammary carcinomas. We found cells with three or more centrosomes in the polyploid tumors. The endocrine unresponsive tumors showed a higher average number of centrosomes per cell than the responsive tumors. The results suggest an association between polyploidy and centrosome amplification with the resistance to endocrine therapy in this luminal breast cancer model.

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.