Medroxyprogesterone Acetate and Metastases: Of Mice and (wo)Men
Authors: V. Craig Jordan
Journal: JNCI Journal of the National Cancer Institute (2005)

The current research strategy for the treatment of cancer is to identify a specifi c target and develop drugs to block tumor growth or destroy cancer cells. This approach must also produce minimal side effects for the patient. Regrettably, it is unlikely that there is a single answer to cancer, but it is hoped that a combination of incremental advances that retard cancer development and progression will, together, create improvements in cancer care. In the case of breast cancer, there has been a two-pronged attack on the disease, and both approaches, which target the estrogen receptor (ER), have had some measure of success in the clinic ( 1 ) . Chemoprevention of breast cancer with the antiestrogen tamoxifen can reduce the incidence of tumors by approximately 50% in high-risk women ( 2 ) . Similarly, preventing the growth of metastases by the appropriate application of adjuvant endocrine therapy following surgery can enhance survivorship substantially ( 3 ) . However, current strategies of exploiting the ER target have probably reached their zenith, and new targets and approaches for achieving cancer-selective toxicity in ERnegative breast cancer are required. Unfortunately, the problem of fi nding and exploiting cancerspecifi c targets for therapy is not new but one that has confounded our best efforts for a century. Paul Ehrlich is the individual who, in the early years of the 20th century, established the scientifi c method of screening chemicals to kill infectious disease selectively without harming the patient ( 4 ) . He successfully developed a chemical therapy (i.e., chemotherapy) to treat syphilis and wanted to use the same principles to treat cancer. The key to Ehrlich’s initial success in antibacterial chemotherapy was to select an appropriate animal model of human disease for testing the chemicals. He used the same logic to address a cure for cancer. At that time, there was suffi cient knowledge to maintain transplantable cancer in repeated generations of laboratory mice He could, therefore, test selective anticancer chemicals for clinical applications. However, his initial hopes were followed by disillusionment. Many of Ehrlich’s results in mice with grafted tumors were confl icting and confusing. In 1915, he admitted defeat and declared “ I have wasted 15 years of my life in experimental cancer. ” He died in August 1915. Today, with the explosion of basic cancer research, we are confronted with a wide range of potential targets for cancer therapy, all of which can be evaluated in mouse models. In this issue of the Journal, Palmieri et al. ( 5 ) have focused their efforts on blunting the calling card of cancer that kills — metastatic colonization. What is interesting about their observations is the proposition that a new target, the glucocorticoid receptor (GR), may be able to be teased out of ER-negative breast cancer and exploited in the future to aid patients. The approach used by Palmieri et al. ( 5 ) employs a mouse model that is generally accepted to parallel the seeding and subsequent growth of metastatic cells in women. Human ERand progesterone receptor (PR) – negative breast cancer cells (MDAMB-231T) were injected intravenously into athymic mice, and the incidence, number, and size of gross pulmonary metastases were measured. The authors report that the synthetic progestin medroxyprogesterone acetate (MPA) reduced colony-forming effi ciency in soft agar by 40% – 50% and reduced metastatic colonization to 73% and 64% of control levels in two separate experiments using athymic mice. MPA is a promiscuous steroid that has predominately progestational activity but also has glucocorticoid ( 6 , 7 ) and androgenic ( 8 ) activity. It is the glucocorticoid-like actions of MPA that turn on the metastasis suppressor gene Nm23-H1 in MDA-MB-231T breast cancer cells ( 9 ) . Transfection of the MDA-MB-231T cells with an antisense Nm23-H1 construct caused a reversal of effects of MPA on colony-forming effi ciency in soft agar. Regrettably, the same experiment was not performed in vivo, creating doubts about the actual role of Nm23-H1 under “ fi eld testing conditions. ” Nevertheless, the authors do show an association between elevations of Nm23-H1 in pulmonary colonies in their MPA-treated mice, although it should be remembered that these are tumor cells that form metastases despite expressing increased levels of Nm23-H1. The central thesis of Palmieri et al. ( 5 ) focuses on the possibility that antimetastatic tumor suppressor genes can be reactivated by MPA, thereby reducing the numbers of metastatic lesions that successfully seed. Fewer metastatic lesions would potentially extrapolate to a lower probability of cancer-related death. If the use of MPA were only a reinvention of the Ehrlich approach to screening compounds (which it is not), one would wonder how MPA could possibly be applied appropriately in women. The received wisdom for breast cancer is that metastatic spread has often already occurred by the time of diagnosis of the primary tumor. This is certainly true of all node-positive breast cancers and is also true for about one-third of node-negative breast cancers. Indeed, early metastatic spread is the basis for all current adjuvant treatment strategies, which aim to destroy the micrometastases that are already established around a woman’s body ( 10 ) . Clearly, the immediate clinical application of a compound that prevents the initial colonization of organs with metastatic cells presents a challenge if it is true that metastatic spread has occurred prior to diagnosis. Be that as it may, this is no less of a challenge than previous efforts to test drugs that block enzymes that affect