Experimental mammary epithelial morphogenesis in anin vivo model: Evidence for distinct cellular progenitors of the ductal and lobular phenotype

Abstract

An in vivo transplantation system has been used to evaluate the developmental capacities of specific mouse mammary epithelial cell populations. Specifically, mouse mammary epithelial cells with distinctly limited developmental potentials have been identified using this procedure. Two distinct epithelial cell progenitors have been identified by experiments designed to determine whether basal lobular and ductal phenotypes could develop independently under conditions imposed by a limiting dilution. The prediction that these separate epithelial progenitors must exist was based upon the results from transplantation experiments carried out in epithelium-divested mammary fat pads of syngeneic mice with mammary epithelium from two different transgenic mouse models. The results presented here demonstrate the following points: 1) lobular, i.e. secretory, progenitor cells are present as distinct entities among the mammary epithelial cells found in immature virgin female mice; 2) similarly, ductal epithelial progenitors are present within the same population; 3) lobular progenitors are present in greater numbers, although both cell populations are extremely small; 4) as expected, some inocula produce outgrowths with simultaneous development of both lobular and ductal phenotypes--it is not known whether this indicates cooperative interaction between the two epithelial progenitors or signals the presence of a third progenitor type capable of producing both ductular and lobular committed daughters; 5) these findings have important consequences in the design of experiments aimed at testing the effects of known and putative mammary oncogenes and tumor suppressor genes, using techniques which include cellular transformation in vitro followed by in vivo cultivation and evaluation.

Stem Cells, Hormones, and Mammary Cancer

“…Similar lobule-limited outgrowths were developed when PI-MEC were inoculated in limiting dilution into the cleared mammary fat pads of subsequently impregnated hosts (Fig.2). These structures like those described earlier [15] comprised both secretory luminal cells and myoepithelial cells and were 100% positive for LacZ activity indicating that they were developed entirely from PI-MEC. Therefore it is likely that PI-MEC arise from the lobule-limited progenitor population discovered by Smith [15] among the mammary epithelial cells present in nulliparous unbred females.…”

“…WAP-Cre knock-in mutants). Second, limiting dilution transplantation assays with dispersed epithelial cells from nulliparous female mice demonstrate the existence of lobule-limited and duct-limited progenitors [15]. These studies were carried out with epithelial cells from WAP-LacZ transgenic mice where LacZ is expressed from the whey acidic protein promoter in late pregnant mice.…”

Impairment of mammary lobular development induced by expression of TGF?1 under the control of WAP promoter does not suppress tumorigenesis in MMTV-infected transgenic mice

“…Another example of the ability of TGF␤1 in inhibiting mammary tumor development was observed in bitransgenic WAP-TGF␤1 x Met-TGF␣ mice. 7 In Met-TGF␣ female mice tumors arise from lobular hyperplasias that persist after involution and subsequently progress to malignancy only after multiple pregnancies. 20 In this case, the fact that Met-TGF␣ exerts its proliferative effect mainly in the lobular progeny, but not in the progenitor (stem) cells is revealed by the fact that these tumors are unable to grow upon transplantation (Smith, unpublished results).…”

“…7 Generally, the surgical procedures required to remove the host epithelium from the fat pads were performed immediately before insertion of the transplant at the 3rd week of age of the female host. Implanted mammary tissue came from females that had gone through at least 5 pregnancies.…”

“…On the contrary, this factor showed mammary tumor suppressor activity in both TGF␤1 transgenic models when crossbred with TGF␣ transgenic or in MMTV-TGF␤1 transgenic DMBA treated mice. 6,7 Mouse mammary tumor virus (MMTV) is a type B retrovirus that causes mammary tumors in susceptible mice. MMTV is transmitted either horizontally as a milk-borne exogenous virus or vertically as a germ-line integrated provirus.…”