HRBC Genomics Network project

Description

Breast cancer is the leading cause of cancer morbidity in women, accounting for close to one fourth of all new cancer cases in the female population; one out of ten women is likely to develop breast cancer in her lifetime.

Despite numerous uncertainties surrounding the origins of these diseases, there is substantial evidence indicating that breast cancer risk relates to endocrine and reproductive factors, as only 5-10% of such tumors can be linked to genetic causes and their genesis and progression depends on the ovary and on endocrine conditions related to ovarian dysfunction. Estrogens are directly involved in the etiology of breast cancer due to their ability to regulate growth of normal and transformed mammary gland cells, where they act as tumor promoters by inducing selection and amplification of mutant (initiated) cell clones.

At the time of diagnosis, a significant fraction of breast cancers are hormone dependent and responsive to endocrine manipulations aimed at interfering with estrogen actions. When first discovered, this notion introduced for the first time in the case of breast cancer the concept that certain biological indicators could be used to predict the effectiveness of a therapeutic regimen, namely endocrine therapy (in this case the presence of estrogen and progesterone receptors in cancer cells).

This is still valid today, although clinical evidences indicate that the receptor status of breast cancer cells is not a sufficient indicator of hormone responsiveness of the tumor. Indeed, endocrine therapy shows a response rate of 30% in unselected patients, of about 50% in ER-positive patients, and of 60-70% if ER/PR are positive. There are thus more than 30% of receptor-positive cancers that, despite all predictions, fail to respond to hormonal treatments, whereas 5-10% of patients with receptor-negative tumors unexpectedly respond. Tumor-specific estrogen receptor dysfunctions, or mutations in their intracellular signalling, are thought to contribute to such discrepancies, but no substantial evidence in this sense is available to date, as many uncertainties still reside on the mechanisms that mediate control of cell proliferation by estrogen in normal and transformed mammary gland cells. In particular, the genes and gene network downstream of estrogens in breast cancer cells are still uncharacterized.

The unifying tool of the project will thus be a growing set of genes that will serve as basis for the design of a common microarray platform, to be used by all RUs carrying out gene expression profiling experiments and regularly updated to include all newly discovered genes, and for the implementation of a database where all data gathered on each individual gene under study (including mechanism of responsiveness to estrogens, antiestrogens and nuclear receptor ligands, pattern of expression/activity of the corresponding mRNA and protein in cell, tissue and tumor samples, relevant cytogenetic and genomic informations and bibliographic references) will be stored and made accessible to all participant laboratories. In addition, a separate database will link patient and gene expression data. These databases, together with the scientific publications and patents produced within the consortium, will represent the main product of this project and an easily accessible and reliable measure of its progresses.