D-type Cyclins are important downstream effectors of cytokine signaling that regulate the proliferation of normal and neoplastic mammary epithelial cells

Abstract

In response to the ligand-mediated activation of cytokine receptors, cells decide whether to proliferate or to undergo differentiation. D-type Cyclins (Cyclin D1, D2, or D3) and their associated Cyclin-dependent kinases (CDK4, CDK6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the G1 restriction point and into the S phase, after which growth factor stimulation is no longer essential to complete cell division. D-type Cyclins are upregulated in many human malignancies including breast cancer to promote an uncontrolled proliferation of cancer cells. After summarizing important aspects of the cytokine-mediated transcriptional regulation and the posttranslational modification of D-type Cyclins, this review will highlight the physiological significance of these cell cycle regulators during normal mammary gland development as well as the initiation and promotion of breast cancer. Although the vast majority of published reports focus almost exclusively on the role of Cyclin D1 in breast cancer, we summarize here previous and recent findings that demonstrate an important contribution of the remaining two members of this Cyclin family, in particular Cyclin D3, for the growth of ErbB2-associated breast cancer cells in humans and in mouse models. New data from genetically engineered models as well as the pharmacological inhibition of CDK4/6 suggest that targeting the combined functions of D-type Cyclins could be a suitable strategy for the treatment of ErbB2-positive and potentially other types of breast cancer.

Keywords: Breast cancer; Cyclin D; ErbB2; Gene targeting; Mammary gland development; Tetracycline transactivator.

Fig. 1. Expression of exogenous Cyclin D1 in the mammary epithelium of Cyclin D1 knockout mice does not accelerate ErbB2-induced mammary tumorigenesis

Immunostaining of Cyclin D1 in histologic sections of normal and hyperplastic mammary ducts as well as mammary tumors of MMTV-neu MMTV-tTA TetO-Cyclin D1 triple transgenic females (A, B), MMTV-neu MMTV-tTA TetO-Cyclin D1 Cyclin D1^−/− mice (C-E), and MMTV-neu Cyclin D1^−/− littermate controls (F). Slides were counterstained with hematoxylin; bar represent 50 μm. Inset in panel C shows a section of the salivary gland, which is serves as a positive control for expression of MMTV-driven transgenes (here MMTV-tTA mediated transactivation of TetO-Cyclin D1).