The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

Abstract

More than 60% of all breast neoplasias are ductal carcinomas expressing estrogen (ER) and progesterone receptors (PR). By contrast, most of the spontaneous, chemically or mouse mammary tumor virus induced tumors, as well as tumors arising in genetically modified mice do not express hormone receptors. We developed a model of breast cancer in which the administration of medroxyprogesterone acetate to BALB/c female mice induces mammary ductal carcinomas with a mean latency of 52 weeks and an incidence of about 80%. These tumors are hormone-dependent (HD), metastatic, express both ER and PR, and are maintained by syngeneic transplants. The model has been further refined to include mammary carcinomas that evolve through different stages of hormone dependence, as well as several hormone-responsive cell lines. In this review, we describe the main features of this tumor model, highlighting the role of PR as a trigger of key signaling pathways mediating tumor growth. In addition, we discuss the relevance of this model in comparison with other presently used breast cancer models pointing out its advantages and limitations and how, this model may be suitable to unravel key questions in breast cancer.

Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer

“…Scores of 2+ and 3+ were considered positive for NuclErbB-2 presence. To assure the specificity of our results, C4HD tumors from the model of mammary carcinogenesis induced by progestins [20] were included in the TMAs. We recently showed a strong NuclErbB-2 localization in these tumors [8] that was completely abrogated by the transfection of a mutant ErbB-2 (hErbB-2ΔNLS) [21] unable to translocate to the nuclear compartment and which acts as a dominant negative inhibitor of endogenous ErbB-2 nuclear migration [8].…”

Estrogen Receptor Alpha Mediates Progestin-Induced Mammary Tumor Growth by Interacting with Progesterone Receptors at the Cyclin D1/MYC Promoters

“…C4-HD tumors were subcutaneously transplanted into MPA-treated BALB/c mice as previously described (10). When tumors reached a size of approximately 50 mm 2 , 6 mice were treated subcutaneously, as described (14), with Fulvestrant (FUL; AstraZeneca), 6 received no other treatment, and the MPA depot was removed in another 6 mice.…”

“…We have previously shown that C4-HD tumors that express ERa and PR grow in MPA-or progesterone (Pg)-treated female mice (10) and that the blockade of PR induces complete tumor regression (23). This experimental system provided an opportunity to explore the role of ERa in progestin-induced tumor growth by using the pure antiestrogen FUL.…”

Targeting Stat3 Induces Senescence in Tumor Cells and Elicits Prophylactic and Therapeutic Immune Responses against Breast Cancer Growth Mediated by NK Cells and CD4+ T Cells

“…All animal studies were conducted as previously described (13), in accordance with the highest standards of animal care as outlined by the National Institutes of Health's Guide for the Care and Use of Laboratory Animals (14), and were approved by the Institute of Biology and Experimental Medicine Animal Research Committee. Hormone-dependent ductal tumor line C4HD was originated in mice treated with 40 mg medroxyprogesterone acetate (MPA; Gador, Buenos Aires, Argentina) every 3 mo for 1 y and were maintained by serial transplantation in animals treated with 40 mg s.c. depot-MPA in the opposite flank to tumor inoculum (15).…”