The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer
- Claudia Lanari,
- Caroline A Lamb,
- Victoria T Fabris,
- Luisa A Helguero,
- Rocío Soldati,
- María Cecilia Bottino,
- Sebastián Giulianelli,
- Juan Pablo Cerliani,
- Victoria Wargon and
- Alfredo Molinolo
- Laboratory of Hormonal Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490 C1428ADN, Buenos Aires, CF, Argentina
- (Correspondence should be addressed to A Molinolo who is now at Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4340, USA; Email: amolinol{at}mail.nih.gov)
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Figure 1
Tumor transplants and generation of tumors. The continuous administration of MPA to female BALB/c mice induces HD mammary carcinomas, which are maintained by syngeneic transplants into MPA-treated mice. Two mice are left untreated to control HD. Occasionally, tumors start to grow in untreated mice and, as a result, a HI tumor is established. These tumors grow even in the absence of MPA. Some of those HI tumors are inhibited by the treatment with antiprogestins (RU486), estrogens (E2) or tamoxifen (TAM; responsive HI: R-PI), and other HI tumors are unresponsive to the hormonal treatment (unresponsive HI tumors: UR-PI).
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Figure 2
Working hypothesis. PR play a key role regulating tumor growth. In HD (PD) carcinomas, MPA or Pg interact with PR inducing a proliferative state characterized by the presence of high levels of stimulating growth factors such as IGF-II and HRG and low levels of inhibitory factors such as TGFβs. If tumors are able to grow without exogenous hormone supply they are considered HI or PI. In these tumors, we have hypothesized that paracrine stromal factors mimic Pg signaling, and therefore, the tumors have a growth pattern similar to PD tumors growing with MPA. FGF-2 is one of the stromal paracrine growth factors inducing PR activation through binding with FGFR-2, its cognate receptor, in the epithelial cells. Therefore, the blockage of PR will induce effects similar to progestin removal in the PD tumors: cytostasis and apoptosis. These tumors are responsive progestin-independent tumors (R-PI) and, as PD tumors, they have higher expression of PR-A than PR-B. However, in some PI tumors, PR inhibition with antiprogestins does not inhibit tumor growth (UR-PI). These tumors still express PR but they have a different pattern of isoform expression, as observed by western blots: higher expression of PR-B than PR-A.
- © 2009 Society for Endocrinology
