ABSTRACT
A long history of scientific interest is associated with the mammary gland because of its
seminal role in infant nutrition and well being, and because it is often afflicted by cancer
development. In fact, before the beginning of the twentieth century, there were already
more than 10,000 scientific references to published articles relating to mammary
biology (1). It was an interest in cancer and cancer development in the breast that
brought about the first series of experiments that led to our current concept of tissue-
specific mammary epithelial stem cells. The occurrence of what appeared to be premalig-
nant lesions of the glandular epithelium led DeOme et al. (2) to develop a biologic system
to recognize, characterize, and study hyperplastic nodules in the mammary glands of
mouse mammary tumor virus (MMTV)-infected mice. These investigators developed a
surgical method for removing the endogenous mammary epithelium from the fourth
mammary fat pad. Subsequently, the “cleared” pad was used as a site of implantation
where suspected premalignant lesions could be placed and their subsequent growth and
development could be observed. Using this approach, they were able to show that both
premalignant and normal mammary implants could grow and fill the empty fat pad
within several weeks. During this growth period, the premalignant implants recapitulated
their hyperplastic phenotype, whereas normal implants produced normal branching
mammary ducts. Serial transplantation of normal and premalignant outgrowths demon-
strated that while normal implants invariably showed growth senescence after several gen-
erations, hyperplastic outgrowths did not. It soon became apparent that any portion of the
normal mammary parenchyma could regenerate a complete mammary tree over several
transplant generations, suggesting the existence of cells capable of reproducing new
mammary epithelium through several rounds of self-renewal. However, it was some
time later before this property was recognized as representative of the presence of
mammary epithelial stem cells (3).
