Abstract A11: Cyclin A expression and endocrine resistance in an experimental model of murine mammary carcinomas

Abstract

Abstract Most of human breast cancers are aneuploid because of chromosome missegregation occurring during mitosis. Deregulation in the control of cell cycle progression is frequently found in mammary carcinomas and is associated with mitotic spindle checkpoint defects and aneuploidy. The Laboratory of Hormonal Carcinogenesis has developed an experimental model of mammary carcinomas by the administration of medroxyprogesterone acetate (MPA) to BALB/c mice. These tumors are metastatic luminal ductal carcinomas, which express estrogen and progesterone receptors (PR) and show different responses to antiprogestin treatment. An association between PR isoform expression and endocrine therapy resistance was found in these mammary carcinomas. Tumors with higher levels of isoform A of PR (PRA) than isoform B (PRB) are inhibited by antiprogestin treatment while those with the opposite ratio are antiprogestin resistant tumors. The cytogenetic analysis of these MPA-induced mammary carcinomas showed that all the diploid mammary tumors respond to antiprogestin treatment, whereas aneuploid mammary tumors can be responsive or resistant to the endocrine therapy. Taking into account that Cyclin A has been related to chromosome instability and has also been involved in PR activation, in this study we evaluated its role in aneuploidy and hormone resistance using the MPA breast cancer model. We analyzed the Cyclin A expression by Western blot (WB) and immunohistochemistry (IHC) in the hormone dependent and the independent (HI) derived variants with different antiprogestin responsiveness and ploidy levels. WB studies revealed for Cyclin A two bands of estimated molecular weights of 52 kDa and 48 kDa in all the mammary tumors analyzed. The 52 kDa form of Cyclin A was overexpressed in the aneuploid unresponsive C4-2-HI tumor (10 fold; p<0.05), whereas the 48 kDa Cyclin A form was overexpressed in the resistant C4-HIR tumor (6 fold; p<0.05), compared to the responsive tumors in the C4 tumor family. On the other hand, both forms of Cyclin A were overexpressed in the resistant C7-2-HIR tumor (52 kDa: 6 fold; 48 kDa: 1.7, p<0.05), while the unresponsive C7-HI tumor expressed higher levels of the 48 kDa form (1.5 fold), as compared to the diploid responsive tumor. No differences were observed in the expression of the 48 kDa form of the cyclin in the mammary tumors of 59 tumor family, although the 52 kDa band was increased in one of the responsive HI tumors. These results were confirmed by IHC analysis of the paraffin sections of these tumors. A higher percentage of Cyclin A positive nuclei was observed in the resistant C4-HIR and C7-HI tumors, compared to the responsive tumors studied. These results suggest that in addition to its role in cell cycle control and its participation in aneuploidy, Cyclin A might be involved in the onset of antiprogestin resistance in the MPA breast cancer model. Citation Format: Melina Bilinski, Claudia Lanari, Victoria T. Fabris. Cyclin A expression and endocrine resistance in an experimental model of murine mammary carcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A11.