BS1-1: Stem Cells, Cancer, and Cancer Stem Cells.

Significant advances in breast cancer prevention and treatment have come from strategies based on knowledge of mammary cell biology and the unique molecular fingerprints of individual tumors. The work I will present concerns the contribution of stem-like cells we and others have found in many breast cancers. It has been proposed that such cells may mediate cancer initiation, perpetuation, and generation of tumor heterogeneity, drug resistance and metastasis. The problem of “intratumoral heterogeneity” is very important to understand, for it provides a plausible mechanism of resistance to targeted therapies and can contribute to metastasis, two critical problems to solve to increase survival and improve cure rates of breast cancer patients. Cancer has been called a caricature of embryogenesis. However, we are not aware of studies to determine whether mammary stem cells arise during mammogenesis, or whether they are only found in the adult. If such cells do arise during development, do they exhibit similarities to the stem-like cells detected in breast cancers? We explored these questions by isolating stem cells from mice, and then studying archival tumor microarrays and human cell lines. We dissected each stage of mouse mammogenesis and determined that fetal mammary stem cells (fMaSC) are not measurable by transplantation analyses early in development. However, they increase in abundance dramatically in late development, at the time when the rudiment invades through the mesenchyme into the adjacent fat pad. The cell surface properties of these cells enabled us to purify them extensively, and determine the genes they express, as well as those expressed in the stroma with which they associate. We found that the fMaSCs have many similarities to aggressive breast cancers, including an impressive enrichment for the fMaSC gene expression program in basal-like breast cancers. Interestingly, the associated fetal stromal (fSTR) cells have similarities to what have been termed “Cancer Stem Cells”, and we found the fSTR signature enriched in the rather rare Claudin-low and metaplastic breast cancers. We have also identified growth regulatory pathways that may provide therapeutic targets for breast cancers exhibiting an fMaSC-like gene expression signature. Our studies establish significant links between the molecular pathways present in both the stem cell containing and the stromal associated compartments of the embryo. How stem-like cells arise in breast cancer, however, still remains an open question. An intriguing possibility is suggested by our observation that breast cancers encoding mutant p53 genes are also highly enriched for stem-like gene expression signatures. We propose that just as p53 deficiency increases the frequency of somatic cell reprogramming, p53 deficiency in breast cancer may enable cancer cells to revert to an embryonic stem-cell state that offers advantages for cancer cell survival, proliferation, and ability to invade adjacent tissue. Funding: This work was funded by grants from the Breast Cancer Research Program of the Department of Defense, the Breast Cancer Research Foundation, Susan G. Komen for the Cure, and the G. Harold and Leila Y. Mathers Charitable Foundation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr BS1-1.