for those still wondering where the PR status fits into all this...

[Lani]

They are finally starting to get some clues...

It seems that PR can act as an activator of signalling pathways (just like her2 can) and that to prevent metastasis it may be necessary to block the PR receptor to prevent initiation of signalling down some of the same pathways her2 uses (eg, MAPK, PI3K/AKT). This seems to hold both for ER+ and ER- tumors that are PR+

Here is the technical jargon:

Mol Endocrinol. 2007 Apr 17; [Epub ahead of print]
Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on PR capacity to activate cytoplasmic signaling pathways.

Carnevale RP, et al

Instituto de Biologia y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, Buenos Aires C1428ADN, Research Area, Institute of Oncology Angel H. Roffo, University of Buenos Aires, C1417DTB Buenos Aires, Argentina, Department of Molecular and Cellular Biology and Pathology, Baylor College of Medicine, Houston, TX 77030.

Accumulating evidence indicates that progestins are involved in controlling mammary gland tumorigenesis. Here, we assessed the molecular mechanisms of progestin action in breast cancer models with different phenotypes. We examined C4HD cells, an estrogen (ER) and progesterone (PR) receptor-positive murine breast cancer model in which progestins exert sustained proliferative response, the LM3 murine metastatic mammary tumor cell line, which lacks PR and ER expression, and human PR null T47D-Y breast cancer cells. Besides acting as a transcription factor, PR can also function as an activator of signaling pathways. To explore which of these two functions were involved in progestin responses, reconstitution experiments in the PR-negative models were performed with wild-type PR-B, with a DNA binding mutant C587A-PR, and with mutant PR-BmPro, which lacks the ability to activate cytoplasm signaling pathways. We found that in a cell context either ER-positive or -negative, progestins induced cell growth and modulation of matrix metalloproteinases-9 (MMP-9) and-2 (MMP-2), and urokinase-type plasminogen activator (uPA) activities, via MAPK and PI-3K/Akt pathways, in cells expressing wild-type PR-B or DNA binding mutant C587A-PR. In contrast, in cells expressing mutant PR-BmPro, progestins did not induce growth. We also found that unliganded PR expression conferred breast cancer cells an in vitro less proliferative phenotype, as compared to cells lacking PR expression. Modulation of this behavior occurred when PR was functioning either as transcription factor or as signaling activator. Finally, we for the first time demonstrated that progestins favor development of breast tumor metastasis via PR function as activator of signaling pathways. Our present findings provide mechanistic support to the design of a novel therapeutic intervention in PR-positive breast tumors involving blockage of PR capacity to activate cytoplasmic signaling.
PMID: 17440047 [PubMed - as supplied by publisher]