The mammary gland is a dynamic organ, capable of extensive growth, regeneration, and remodeling. The growth demands placed on the mammary gland during embryonic development and throughout adulthood, suggests a function for mammary stem/progenitor cells. Indeed, functional testing of mammary stem cell activity in rodent models has revealed the presence of sub-populations of cells with the ability to recapitulate adult mammary gland development. As yet, there are no markers known that are specifically expressed only by stem cells that can reveal their activation or distribution. Although the contribution of mammary stem cells to breast cancer has yet to be determined, it has been proposed that these cells may play a significant role in mammary tumorigenesis.
Mammary glands are secretory organs derived from the epidermis, which are unique to all members of the class Mammalia. Mammary glands exist in both female and male mammal species, although in males the mammary glands are rudimentary and nonfunctional. In females, the mammary gland consists of a branching network of ducts embedded in a fat pad, which coalesce at the nipple and respond to local and humoral factors to produce milk in response to suckling.
GROWTH DEMANDS FOR MAMMARY epithelial CELLS
There are four processes that demand cell growth and may be mediated by embryonic or adult mammary stem cells: (1) Specification and invag-ination of the embryonic mammary placode. Embryonic specification of mammary placodes starts along two epithelial ridges, known as milk lines, that are formed in the epidermis. Mammary rudiments are formed by further invagination of the ectoderm to form simple ductal structures, which are present at birth. (2) Expansion of the ductal tree during colonization of the mammary fat pads in juveniles. Ductal outgrowth occurs in response to the female endocrine environment, and is led by specialized, proliferative centers called terminal end buds. The mitotic index is very high in the terminal end buds, and it is likely that the ductal stem cells are concentrated in these structures. In the adult these growth centers regress. Ducts comprise heterogeneous cells, broadly divided into a basal layer of myoepithe-lial cells that produce and adhere to the basement membrane, and a single layer of suprabasal luminal cells, that face the ductal lumen. Luminal cells can have multiple layers in actively dividing juvenile tissues and preneoplastic conditions. (3) Cycle-associated proliferation. The hormonal cycles typical of mammalian females can generate mitotic indices in mammary epithelia that are typical of pregnancy, but only briefly (hours long), and the proliferative phase is followed by regression and cell apoptosis. (4) Expansion and differentiation during pregnancy, to produce the lactation-competent mammary gland.
During pregnancy, postcoitus, proliferative humoral signals (from pituitary, ovary, and placenta) induce the extensive proliferation of the lobuloalveoar lineage, which branch off from the permanent adult ductal structure. Postpartum, the luminal epithelial cells terminally differentiate to produce milk (by apocrine secretion) and the myoepithelial cells contract in response to oxytocin (to express milk). During weaning, the majority of lobuloalveolar cells involute. During pregnancy, the mitotic index rises to almost 30 percent continuously.
mammary stem cell assay
To date (November 2007), there is no known marker specifically expressed by mammary stem cells, and so they have not been directly visualized during growth, differentiation or neoplasia. There is, however, a functional assay for rodent mammary stem cell activity, which is the transfer of whole populations (using limiting dilutions) or purified subpopulations, into cleared fat pads (the isotopic growth site) of juvenile (or adult) rodents.
Using immunoincompetent hosts and stro-mal support, human breast stem cells can also be assessed this way. Results obtained from fat pad assays suggest that stem cell activity does not change with age or parity of the female gland, but that it is reduced after serial regeneration of ductal trees. Using flow cytometry, some investigators have purified cell populations enriched for their stem cell activity. In fact, they claim that just one cell can seed the growth of a completely new ductal tree, and this new tree includes a normal component of both mammary lineages.
This fits the operating definition of a stem cell. From limiting dilution assays, the frequency of stem cells can be inferred, and that is found to remain constant at approximately 1:1,400. Since this frequency is also typical of glands after serial transplantation, it is inferred that mammary stem cells can divide symmetrically, and that their proportion in the final population is maintained and constant.
MAMMARY STEM CELLS AND BREAST CANCER
As for other tumors, it is very attractive to propose that somatic stem cells are a fast track precursor cell for mutation. To date, there is no clear evidence for recruitment of normal somatic cells, though it may be true that breast tumors have cancer stem cell subpopulations.
If these cells have properties in common with other cancer stem cells, their growth, response to damage (for example, genotoxins), and death may be regulated by different means than the tumor majority, and their successful elimination will need a separate treatment protocol.
