Intrinsic cues and hormones control mouse mammary epithelial tree size.

Organ size control is a long-standing question in biology. In mammals, using conditional cell ablation, two mutually exclusive mechanisms involving either intrinsic or extrinsic programs have been described to control organ size. The mammary gland is an ideal model for such studies, since it undergoes size and morphological changes during puberty and pregnancy. The role of stem cells in controlling mammary epithelial tree size is unclear, although mammary stem cells are able to reconstitute a functional organ on transplantation. Here, we show that mammary gland cellularity was strictly dependent on mammary stem cell number, even following a 20-fold expansion of the mammary stem cell pool at puberty and transient 3-fold expansions with each pregnancy. In addition, the expansion of the mammary stem cell pool was hormone dependent, as demonstrated by female bilateral ovariectomies during puberty and transplants of male-derived cells into female recipients. In these transplants, apart from a mammary stem cell expansion, we also observed the donor cells reconstituting functional mammary glands, developing alveolar structures, and secreting milk after the recipient's parturition. Taken together, these data suggest that in the mammary gland, there is a third organ size control mechanism, combining intrinsic cues throughout the organism's lifetime, with extrinsic hormone signals at particular developmental windows (puberty, pregnancy), where an expansion of the mammary stem cell pool occurs. This mechanism might have strong implications for the understanding of mammary tumorigenesis, since the expansion of the mammary stem cell pool precedes the generation of breast tumors.