Seminar

Humanization of the mouse mammary gland with preneoplastic human cells

Prof. Richard Iggo

The cell of origin for estrogen receptor  (ER) positive breast cancer is probably a luminal stem cell in the terminal duct lobular units. To model these cells we have used the murine myoepithelial layer in the mouse mammary ducts as a scaffold upon which to build a human luminal layer. Normal human cells are quickly lost after intraductal injection but cells infected with lentiviruses expressing CCND1, MYC, TERT, BMI1 and a short hairpin RNA targeting TP53 progressively replace the luminal layer in the mouse mammary ducts, resulting in the formation of an extensive network of humanized ducts. Despite expressing multiple oncogenes, the human cells form a morphologically normal luminal layer. Expression of a single additional oncogene, PIK3CA-H1047R, converts the cells into invasive cancer cells. The resulting tumors are ER+, Ki67+ luminal B adenocarcinomas that are resistant to treatment with fulvestrant. Genetic manipulation of cells injected directly into the mammary ducts makes it possible to study defined steps in the transformation of human mammary epithelial cells in a more physiological environment than has hitherto been possible.