ESTROGENS AND BREAST CANCER

Breast cancer is the most frequent neoplasia in North American women and the second cause of cancer-related deaths after lung cancer. The causes of breast cancer remain unknown but it is well known that the female sex hormones, estrogens, stimulate the proliferation of human breast cancer cells. The objective of our research project is to identify cellular genes that are involved in the mitogenic effect of estrogens. To this end, we are using two complementary approaches: the study of the hormonal regulation of known regulators of cell growth, and the identification of novel estrogen-responsive genes.

Our work to date has focussed on the gene products involved in cell cycle control. In these studies we use experimental models of human breast cancer cells grown in vitro as well as in vivo. We are particularly interested in the interactions between estrogens and cyclin-dependent kinase (Cdk) inhibitors such as p21, which halts cell cycle progression in G1. We have found that estrogens down-regulate p21 expression both in vitro and in vivo. Given the role of p21 in cell cycle control, these results suggest that neutralisation of p21 is required for the mitogenic effect of estrogens. We have also studied the Cdk inhibitor p18 and have identified a novel inactivating mutation of this gene. We have subsequently cloned the human p18 gene and are currently investigating it to further understand its role in the control of breast cancer cell cycle and its interactions with estrogens.

To better understand estrogen activity, it is important to directly isolate genes whose expression is regulated by estrogens, in the hope that these genes will be involved in the control of cellular proliferation. To do so, we will use differential display PCR and differential cDNA library screening.

In parallel with these experiments we are studying the biological properties of a potent new nonsteroidal antiestrogen, EM-800. Since this molecule is a pure antagonist, EM-800 serves as a powerful research tool in studying estrogen-dependent gene regulation.

These projects are supported by the Fonds de la recherche en santé du Québec and the Canadian Breast Cancer Research Initiative.

Blais A, Labrie Y, Pouliot F, Lachance Y, Labrie C (1998) Structure of the gene encoding the human cyclin-dependent kinase inhibitor p18 and mutational analysis in breast cancer. Biochem Biophys Res Comm, in press.