Mammary Stem Cells
(Lay Summary)

Breast cancer is the most common form of cancer in women, and every year hundreds of thousands of women are newly diagnosed (American Cancer Society 2006).  Most breast cancers originate in the mammary ducts, while a smaller subset originates in the lobules (Colditz 1993).  Since cancer is a stem cell disorder, understanding the basic stem cell biology of mammary cells will help researchers find treatments and maybe even a cure for breast cancer.

Prior to sexual maturity, the mammary gland consists of a rudimentary ductal system.  Enhanced secretions of estrogen at puberty help develop the mammary ductal system.  The basic functional units of the branching ducts of the mammary gland are terminal ductal lobulo-alveolar units (TDLUs).  Luminal or ductal epithelial cells form the inner layer of the ducts, while myoepithelial cells compose the outer basal layer of the ducts.  During pregnancy, estrogen and progesterone cause further branching of the ductal system and the development of milk-secreting structures known as lobules.

Figure 1.  Basic breast anatomy.  Breast profile: A) Ducts, B) Lobules, C) Dilated section of lobules, D) Nipple, E) Fat, F) Pectoralis Major Muscle, and G) Chest wall/rib cage.

Mammary stem cells (MaSCs) have a fundamental role in the regeneration of mammary tissues during cycles of pregnancy, lactation and involution.  In the mammary epithelium of mice, the number of potential MaSCs is approximately 1 in 2,500 cells (Smith 1996, Kordon 1998).  The existence of MaSCs in mice has been confirmed by various experiments (Smith 1996, Shackleton 2006, Kordon 1998, Tsai 1996).  It has been shown that MaSCs are found throughout the fully developed mammary gland (Kordon 1998).

The existence of a pluripotent progenitor of three self-renewing, multipotent epithelial cells (lobule-limited, ductal-limited, fully competent) has been suggested (Smith 2002, Smith 1996).  Lobule-limited stem cells are able to produce secretory lobules, while ductal-limited stem cells are able to produce mammary ducts.  Fully competent mammary stem cells have the ability to generate the entire mammary epithelium.  The exact lineage of mammary stem cells has not been entirely determined, but a couple of models have been proposed (Figure 2). 

Figure 2. Possible lineages of mammary stem cells.

In order to distinguish mammary stem cells from other cells, distinctive characteristics that MaSCs possess have to be revealed.  Identifying these unique markers will aid in future research and possibly play an important role in breast cancer treatment.  MaSCs have been described as pale or light-staining cells (Smith 1988).  They can either be undifferentiated large light cells (ULLC) or small light cells (SLC) (Chepko 1997).  These stem cells possess molecular markers such as CD29, CD24, CD49f and Sca-1 (Shackleton 2006, Stingl 2006, Welm 2002).  Markers present on MaSCs might play an important role in homing and maintenance of these stem cells.  MaSCs also express epithelial-specific antigen (ESA) and keratin K19, but are negative for sialomucin (MUC-1).  In addition, MaSCs can either be estrogen receptor positive (ER+) or estrogen receptor negative (ER-) (Gudjonsson 2002). 

MaSCs are located throughout the mature mammary gland (Kordon, 1998).  ULLC are located between the basal and luminal layer of the mammary gland, and they possess large nuclei.  SLC, on the other hand, have been located in the basal layer (Chepko 1997). 

There is strong support for the presence of multipotent tumorigenic stem cells within leukemia (Bonnet 1997) and solid tissue tumors including breast (Singh 2004, Galli 2004, Ponti 2005).  Upon transplantation, these self-renewing, tumor initiating cells give rise to additional tumorigenic stem cells as well as a mixed population of differentiated, non-malignant cells (Reya 2001).  Breast cancer cells were found to generate tumors in mice (Al-Hajj 2003), and have since been estimated to represent 10-20% of total cells in a breast tumor population (Abraham 2005). Breast cancer stem cells have also recently been identified in tumor cells present in the bone marrow of early breast cancer patients (Balic 2006).  This suggests that breast cancer stem cells are able to migrate outside of the breast.

The origin of cancer stem cells is unclear, and tumorigenic stem cells may arise from normal stem cells or progenitor cells that acquire the capacity for self-renewal (Kristov 2006).  Other models surmise that tumor initiating cells are the result of cell-cell fusions or phagaocytic gene-transfer from tumor cells (Bjerkvig 2005, Bergsmedh 2001).  Data supports that tumor initiating cells in the breast are phenotypically similar to early multipotent epithelial cells (Gudjonsson 2002, Stingl 1998, Aigner 1997) and that ER+ breast cancers likely originate in ER+ ULLC mammary stem cell populations (Clarke 2005, Gudjonsson 2002).  Gene pathways implicated in the regulation of stem cell self-renewal are tightly regulated in normal stem cells, and disruption of these pathways appears essential for development of tumor initiating cells (Bjerkvig 2005, Al-Hajj 2004).

The presence of rare cells in breast cancers responsible for tumorigenesis indicates the need of targeted therapeutics capable of selectively addressing the malignant cell population.  Specific cell surface markers have been identified for mammary stem cells and breast cancer stem cells, opening the way for vastly improved, targeted cytotoxic therapies and accurate breast cancer diagnostics.  However current tools are not readily available to exploit the full potential of these findings.  Hopefully, these shortcomings will be ameliorated through continued efforts in the promising field of stem cells.

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Summarized by:  Joyce Kim, Jason Moore and Ajitha Patlolla, Graduate Course in Stem Cell Biology, Fall 2006

Teaching Assistant: Steve Greco