Antitumor action of physiological estradiol on tamoxifen-stimulated breasttumors grown in athymic mice

The estrogen receptor (ER)-positive MCF-7 breast cancer cell line can be tr ansplanted into athymic mice and grown into tumors with estradiol (E-2) sup port. Tamoxifen (TAM) blocks E-2-stimulated tumor growth; however, continuo us TAM treatment results in transplantable tumors within a year that will g row with either E-2 or TAM (M. M. Gottardis and V. C. Jordan, Cancer Res., 48: 5183-5187, 1988), Although this model map represent the development of TAM resistance for the treatment of advanced breast cancer, no laboratory m odel exists to study the exposure of breast cancer to 5 years of adjuvant T AM therapy. We have addressed this issue and report the development and cha racterization of two tumor lines, MCF-7TAM and MT2, which have been seriall y transplanted into TAM-treated athymic mice for >5 years. The MCF-7TAM tum or rapidly regresses in response to E-2 and then about 50% of tumors regrow in response to E-2. Interestingly, tumor regression does not occur if TAM treatment is stopped, probably because E-2 levels are too Low in ovariectom ized athymic mice. The development of the antitumor effect of E-2 was docum ented for MT2 tumors over a 1-year period; TAM-stimulated tumor growth was retained, but E-2 caused progressively less of a stimulatory effect. Most i mportantly, E-2-stimulated tumors that regrew after initial tumor regressio n in both MCF-7TAM and MT2 lines were again responsive to TAM to block E-2- stimulated growth. Unlike MCF-7 tumors, the MT2 tumor Line contains a singl e point mutation, Asp351Tyr, in the ER, which was retained after the develo pment of E-2-stimulated regrowth. The mutation is associated with increased estrogen-like actions for the TAM-ER complex (A. S, Levenson ef al., Br, J , Cancer, 77: 1812-1819, 1998), but me conclude that the mutant ER is not r equired for TAM resistance. On the basis of the new breast cancer models pr esented, we propose a cyclic sensitivity to TAM that may have important cli nical implications: (a) it is possible that a woman's own estrogen may prod uce an antitumor effect on the presensitized micrometastatic disease after 5 years of TAM. Long-term antitumor action occurs because the drug is stopp ed, but resistance accumulates and tumors start to grow if adjuvant therapy is continued; and (b) although in the clinic TAM-resistant tumors respond to second-line therapies that cause estrogen withdrawal, e.g., pure antiest rogens or aromatase inhibitors, estrogen therapy may also be effective and return the tumor to TAM responsiveness. In this way, a hormone-responsive t umor mag be controlled longer in the patient with advanced disease.