Discovery of candidate genes and pathways that may help explain fertility cycle stage dependent post-resection breast cancer outcome.

Breast cancer relapse and death occur more often and sooner among young pre-menopausal women. Breast cancer resected during luteal phase cures about a quarter more women than if the operation is performed during follicular phase. We have identified candidate breast cancer gene signatures that may point to the potential mechanisms of cycle stage-dependent surgical cure. We performed whole murine genome microarrays on mammary tumors resected during pre-ovulatory (diestrus, follicular) and post-ovulatory (estrus, luteal) phases of the estrous cycle with known post-surgical cure or relapse (pulmonary metastasis) outcome. A set of genes whose expressions are differentially modulated by fertility cycle stage of tumor resection and also associate with prognosis were identified. These identified genes were validated by qRT-PCR. From two independent microarray studies, we identified 90 genes in mammary tumors whose expressions change significantly (up to 100-fold) across the estrous cycle, 69 genes that are associated with cure/relapse independent of cycle stage at resection, and 24 genes that change significantly (up to 12-fold) across the estrous cycle and also associate with the outcome. The mRNA expression patterns of these 24 identified genes were 100% validated by qRT-PCR in the same samples. We have identified candidate breast cancer genes and pathways that may point to the potential mechanisms by which the post-resection breast cancer outcome is influenced by the menstrual cycle phase of cancer resection. Since human breast cancer outcome is influenced by the menstrual cycle phase of breast cancer resection, we consider this study in a mouse breast cancer model to be a proof of principle that such signatures may well exist in human premenopausal breast cancer. It remains to be determined in human breast cancer whether woman to woman and/or tumor to tumor variability will mask cycle phase dependent and outcome predictive genomic signatures in human premenopausal breast cancer. The pathways identified by these studies are potential targets for the development of peri-surgical neoadjuvant therapies, which may delay or prevent relapse by preventing dormant micrometastatic tumor cells from escaping that dormant state post-operatively.