Origin and Progression of Pregnancy-Dependent Mammary Tumors Induced by New Mouse Mammary Tumor Virus Variants

Abstract

In order to study mechanisms of progression of mouse mammary tumor virus (MMTV)-induced pregnancy-dependent mammary lesions, we removed and serially transplanted 17 small tumors detected in MMTV-infected pregnant females. This gave rise to the same number of 'in vivo' tumor lines. Hormone-dependency of the passages was determined by comparing tumor development in multiparous versus virgin hosts. We found that the first passages of most of these lesions (11/17) required pregnancy to grow. However, all these tumor lines lost their hormone-dependence through successive passages. The original pregnancy-dependent lesions were mostly multiclonal and showed high levels of estrogen and progesterone receptors. Alternatively, pregnancy-independent tumors arose as clonal dominant populations exhibiting a lower hormone receptor content. Our data show that the progression of hormone-dependent MMTV-induced mammary tumors is an irreversible process associated with the appearance of additional MMTV insertional events as well as alterations in the composition of the tumor cell population.

Progression of Pregnancy-Dependent Mouse Mammary Tumors after Long Dormancy Periods. Involvement of Wnt Pathway Activation

“…The results showed herein confirm our previous data showing that in BALB/c, PD MMTV(LA)-induced mammary lesions can arise from polyclonal cell populations, although PI tumors are mostly monoclonal (7). Similarly, it has been demonstrated that hormonedependent GR mouse mammary tumors are oligoclonal with respect to MMTV production (28), extra MMTV integration (18,29), DNA rearrangements, and gene activation (22).…”

“…Animal care was in accordance with institutional guidelines. Procedures to generate and follow in vivo tumor lines as well as tumor DNA extraction and Southern blot analysis have been described previously (7).…”

“…Similar to what was reported previously in BALB/cfRIII mice (6), most of these tumors regress partially or even completely after delivery to reappear at the same site in subsequent pregnancies. Eventually, they become autonomous and grow independently of the female hormonal status (4,7).…”

Selection of Early-Occurring Mutations Dictates Hormone-Independent Progressionin Mouse Mammary TumorLines

“…Infected pregnant females were examined in order to detect pregnancy-dependent primary tumors. Individual tumors (tumor area, ϳ50 mm 2 ) were minced in sterile phosphate-buffered saline, and randomized fragments of 1 to 2 mm 3 were transplanted subcutaneously by trocar in the flanks of syngeneic females that were either maintained in a virginal state or crossbred. Three to eight consecutive tumor passages were made in order to investigate their eventual progression to pregnancy independence.…”

“…We have previously shown that PD tumors frequently arise as polyclonal populations, while their PI derivatives appear in subsequent transplant generations as monoclonal cell populations. In addition, the latter frequently display MMTV insertions undetected in the corresponding PD by Southern blot analysis (3).…”