One of the key challenges to breast cancer research has been to create a realistic model of this disease. Bob Weinberg and colleagues now report a new method for reconstructing human mammary epithelium in mice, which highlights the importance of the stroma in breast tumorigensis.

The authors hypothesized that establishing human mammary stroma within the mouse mammary fat pad would provide a suitable environment for the human mammary epithelial cells (MECs) to grow. To do this, they injected a mixture of irradiated and non-irradiated mammary stromal fibroblasts into the mammary fat pads of immunocompromised mice — irradiation has been previously shown to activate expression of proteases, matrix proteins and growth factors in fibroblasts. Subsequent injection of a mixture of human breast fibroblasts and human MECs prepared from histologically normal human reduction mammoplasty tissues into the humanized stromal fat pads led to development of human epithelial growths with acinar, ductal and lobular structures. Weinberg and colleagues observed that this human breast tissue was fully functional during pregnancy — the cells were histologically normal, and synthesized and secreted lipids into the lumina of the human acini.

When human MEC preparations isolated from patients who had undergone mammoplasty were introduced into the humanized stromal fat pads without addition of primary human mammary fibroblasts, 30% of the samples underwent hyperplastic ductal growth. This indicates that the primary human fibroblasts suppress hyperplasia.

Two growth factors synthesized by mammary stromal cells are overexpressed by human breast cancer cells — hepatocyte growth factor causes hyperproliferation of mammary epithelium, and transforming growth factor-β1 inhibits proliferation of stromal cells and induces neoangiogenesis. The authors observed that when either of these factors was ectopically expressed in the humanized stromal fat pads, some of the injected human MEC cells that were isolated from mammoplasty samples developed into invasive and poorly differentiated carcinomas. Surprisingly, if MECs taken from the same patient but from different regions of the mammoplasty tissue were used, no carcinoma was formed.

The authors suggest that the reduction mammoplasty MECs must have included cells that were already abnormal when removed from the donor mammary gland (although this was undetectable by histology) and that these cells then thrived in the altered stromal environment. This model provides a new way of studying human breast cancer pathogenesis.