Clusterin is a secreted glycoprotein,upregulated in many physiological and pathophysiological conditions that has been proposed to play a role in tissue remodeling and apoptosis. Although clusterin in the mammary gland has not been extensively studied, clusterin has been implicated in mammary gland development and in breast cancer progression. To address the role of clusterin in murine mammary gland development, mammary morphogenesis was monitored in clusterin knockout (CLUKO) and wild-type mice. The ablation of clusterin alters ductal outgrowth, ductal branching, terminal end bud growth, rates of mitosis and apoptosis, and gland mass. This leads to precocious pubertal mammary gland development.
In several pathophysiological conditions such as cancer it is unclear whether the upregulation of clusterin is directly involved in the process of apoptotsis, whether its induction is secondary to stress and/or apoptosis, or whether the protein is induced as a protective or survival mechanism for the cell in response to stress. We have shown that the biogenesis of clusterin in MCF-7 breast cancer cells is significantly altered after treatment with TNF-a or the antiestrogen tamoxifen, leading to an upregulation of clusterin and the appearance of a non-glycosylated isoform of clusterin in the nucleus. Overexpression of the wild-type and nuclear isoforms of clusterin in vitro demonstrates a role for clusterin in the regulation of tumor cell growth. Clusterin appears to protect cells from apoptosis, and contributes to an invasive phenotype. In vivo work has established that clusterin overexpression increases tumor size, provides resistance to tamoxifen and facilitates the progression to a metastatic phenotype. All of these characteristics are common to the highly aggressive phenotype observed in late stage breast cancer patients.
These data are the first to clearly demonstrate that clusterin plays a role in pubertal mammary gland development and also helps to accelerate the progression of human breast cancer to a more invasive drug-resistant phenotype.