Abstract 2379: Cyclin D3 is important for ErbB2-induced mammary cancer initiation and progression in the absence of Cyclin D1

Abstract

Abstract The cell cycle regulatory protein Cyclin D1 has been reported to be essential for both normal mammary gland development during pregnancy and the malignant transformation of the mammary epithelium in response to receptor tyrosine kinase (RTK) signaling. We have recently reported that the prolactin receptor-associated kinase Jak2 controls the transcriptional activation and, more importantly, the nuclear accumulation of Cyclin D1 in normal mammary epithelial cells via expression and activation of Akt1. We also demonstrated that the functional ablation of Jak2 and Stat5 in ErbB2-expressing mammary epithelial cells protects against the onset of mammary tumorigenesis. Jak2, however, is not required for the survival and proliferation of neoplastic cells. The constitutive activation of ErbB2 signaling, which is an initial event in the formation of mammary cancer in this model, was able to override the functional role of Jak2 in regulating the expression of Akt1 and Cyclin D1. To further define the role of the downstream effector Cyclin D1 during cancer initiation and progression in response to Jak2 and RTK signaling, we generated an ErbB2-associated mammary cancer model that allows a functional ablation of Cyclin D1 either prior to or following neoplastic transformation. Surprisingly, and in sharp contrast to previous reports, nearly all Cyclin D1-deficient females expressing wildtype ErbB2 developed mammary tumors. While Cyclin D1 deficiency extended the tumor-free survival, this particular cell cycle regulatory protein was clearly not required for tumor maintenance and progression. Growth and proliferation of the vast majority of Cyclin D1-deficient primary mammary cancers was accompanied by an upregulation of Cyclin D3. Since Cyclin D2 expression remained very low, knocking down the last remaining D-type cyclin (i.e. Cyclin D3) in tumor-derived primary cancer cells using three different shRNA constructs was sufficient to attenuate the proliferation rates. Interestingly, the ablation of the pool of all three D-type cyclins did not result in an upregulation of Cyclin E. Collectively, the results of this study show that Cyclin D1 is dispensable for neoplastic transformation of mammary epithelial cells and it might therefore not serve as a sole therapeutic target to treat ErbB2-associated breast cancers as previously suggested. In addition, these observations indicate that Cyclin D1 is most likely not the only downstream effector of Jak2 signaling that mediates the protective effects of a functional ablation of Jak2 in ErbB2-induced mammary carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2379. doi:10.1158/1538-7445.AM2011-2379