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Chair(s): Barcellos-Hoff, Mary Helen
(SY025) Breast cancer stem cells - biology and therapeutic implications.
Dontu, Gabriela *,1, Liu, Suling1, Wicha, Max, 1 Internal Medicine/Hematology-Oncology, Ann Arbor, MI
ABSTRACT- Introduction There is increasing evidence that a variety of neoplasms, including breast cancer, may result from transformation of normal stem and progenitor cells. Consistent with this model of carcinogenesis, a breast cancer stem cell population, with the phenotype CD44+ CD24-lineage-, was recently identified utilizing flow-cytometry based cell sorting and NOD/Scid mice xenografts. As few as 200 cells of this cancer stem cell population were capable of generating tumors in animals, whereas the bulk of the tumor population was tumorigenic only when implanted in high numbers. A key-event in carcinogenesis is the deregulation of self-renewal in stem cells or the acquiring of self-renewal capability by the progenitor cells. Indeed, signaling pathways that govern the self-renewal of normal breast stem cells, such as Notch, Wnt, Sonic Hedgehog, have all been implicated in carcinogenesis. Results In order to determine the role of Notch and Hedgehog signaling in mammary cell fate determination, we have utilized a newly-described in vitro system in which mammary stem/progenitor cells can be cultured in suspension as non-adherent mammospheres. Utilizing this system, we demonstrate that Notch and Hedgehog signaling can act on mammary stem cells to promote self-renewal and early progenitor cells to promote their proliferation. Conclusions These studies suggest Notch and Hedgehog signaling may contribute to mammary carcinogenesis by deregulating self-renewal of normal mammary stem cells. Based on the stem cell concept, we propose a model of carcinogenesis in which the transformation of different subsets of stem and progenitor cells results in the diversity of breast cancer phenotypes, including the expression of estrogen receptor in subtypes of breast cancers. This model has important implications for understanding mammary carcinogenesis. Furthermore, the concept of breast cancer as a disease of mammary stem and progenitor cells has profound implications for the development of new strategies for breast cancer prevention and therapy.
Key words: stem cells, breast cancer, self-renewal, carcinogenesis
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