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]

[Donna]

Hi Lani,

What agent works against a PR+ tumor? Does the A/C/T regimen address this, do you know? Never paid much attention to the PR part.

Have a great day - and thanks for your always interesting and insightful posts!

Donna

[Margerie]

Yes, thank you for the post!

Wondering the same- anything we can do to decrease progest. in our bodies? Where is this hormone produced anyway? I will try to find out. I had an ooph and hope the ovaries are the only source. I am also wondering why it suggested that women with pr- tumors have more recurrences.

[Lani]

so somewhat short of time to answer. Will do so once technical "challenges" more under control. What I can already tell you is that this is a very poorly understood and under researched area but there are leads and I will follow them up.

Thanks for your responses.

[Margerie]

hard drive disintegration- I usually use more colorful language- LOL.

I did find that progesterone, like estrogen, is primarily produced in the ovaries and is also, to a much lesser extent, produced by the adrenal glands.

[RobinP]

"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]"

Many with her2+ bc have hormonal negative cancers which means that the tumor neither has estrogen or progesterone receptors. I would assume that only pr+ sensitive bc with progesterone receptors would be sensitive to progesterone. Also, I would think that eliminating progesterone would only benifit those with the progesterone receptor.

[AlaskaAngel]

The article discusses "progestin". The question is, is the "progestin" referenced in the article synthetic, or not?

http://www.project-aware.org/Resource/articlearchives/differences.shtml

"Another immediate difference...
between medroxyprogesterone and natural progesterone is that the synthetic hormone can actually lower a patient's blood level of progesterone."

-A.A.

[Hopeful]

Progestin Regulation of Vascular Endothelial Growth Factor in Human Breast Cancer Cells<SUP>1</SUP>

</NOBR><NOBR>Salman M. Hyder<SUP>2</SUP></NOBR>, <NOBR>Lata Murthy</NOBR> and <NOBR>George M. Stancel</NOBR>



Department of Integrative Biology, Pharmacology and Physiology, University of Texas Health Sciences Center-Houston, Houston, Texas 77225



<!-- ABS -->Vascular endothelial growth factor (VEGF) is a potent angiogenic<SUP> </SUP>factor associated with the degree of vascularity, progression,<SUP> </SUP>and metastasis of breast cancer, and cases of this disease with<SUP> </SUP>increased vascular density have a poor prognosis. We show that<SUP> </SUP>in T47-D human breast cancer cells, progesterone induces a dose-dependent<SUP> </SUP>increase of 3-4-fold in media VEGF levels, with a maximum response<SUP> </SUP>occurring at a concentration of 10 nM. This effect is blocked<SUP> </SUP>by the antiprogestin RU 486. In addition to progesterone, a<SUP> </SUP>number of synthetic progestins used in oral contraceptives (e.g.,<SUP> </SUP>norethindrone, norgestrel, and norethynodrel), hormone replacement<SUP> </SUP>therapy (medroxyprogesterone acetate), and high-dose progestin<SUP> </SUP>treatment of breast cancer (megestrol acetate) also increase<SUP> </SUP>VEGF in the media of cultured T47-D cells. This effect is hormone<SUP> </SUP>specific and is not produced by estrogens, androgens, or glucocorticoids.<SUP> </SUP>Collectively, these observations suggest that the increase in<SUP> </SUP>VEGF caused by progestins is mediated by progesterone receptors<SUP> </SUP>present in T47-D cells. The induction of VEGF by progestins<SUP> </SUP>is also cell type specific and does not occur in human breast<SUP> </SUP>cancer cell lines MCF-7, ZR-75, or MDA-MB-231, nor in Ishikawa<SUP> </SUP>cells derived from a human endometrial carcinoma. This is the<SUP> </SUP>first report that progestins regulate VEGF expression in human<SUP> </SUP>breast cancer cells and raises the possibility that increased<SUP> </SUP>angiogenesis in response to endogenous progesterone or its therapeutically<SUP> </SUP>used analogues may play a role in cell growth or metastasis<SUP> </SUP>in a subset of human breast tumors.<SUP> </SUP>

<!-- FN --><!-- null --><SUP><SUP>1</SUP></SUP> Supported by NIH Grants HD-08615 and ES-06995.<SUP> </SUP>

<!-- null --><SUP><SUP>2</SUP></SUP> To whom requests for reprints should be addressed, at Department<SUP> </SUP>of Integrative Biology and Pharmacology, University of Texas<SUP> </SUP>Health Sciences Center-Houston, P.O. Box 20708, 6431 Fannin,<SUP> </SUP>Houston, TX 77225. Phone: (713)-500-7459; Fax: (713)-500-7455;<SUP> </SUP>E-mail: shyder@farmr1.med.uth.tmc.edu.<SUP> </SUP>Received 11/26/97. Accepted 12/16/97.

Link: http://cancerres.aacrjournals.org/cgi/content/abstract/58/3/392

Hopeful

[Becky]

Nice find Hopeful.

[AlaskaAngel]

Interesting, Hopeful -- thanks for posting.

I wonder what the percentage for the prevalence in the human population is for each type of bc mentioned.

If it does occur for T47-D cells, but as noted, "The induction of VEGF by progestins<SUP> </SUP>is also cell type specific and does not occur in human breast<SUP> </SUP>cancer cell lines MCF-7, ZR-75, or MDA-MB-231, nor in Ishikawa<SUP> </SUP>cells derived from a human endometrial carcinoma" then unless T47-D cells are quite prevalent in the human population, maybe progesterone has no negative effect on the majority of bc?

AlaskaAngel

[Hopeful]

AlaskaAngel,

Interesting question. This thread posted by Lani came to mind: http://her2support.org/vbulletin/showthread.php?t=25292&referrerid=1173

Hopeful

[Lani]

HORMONAL INTERACTIONS ARE COMPLEX WITH LOTS OF NEGATIVE FEEDBACK MECHANISMS--HERE YOU SEE THAT PROGESTERONE DECREASES
THE INCIDENCE OF DEATH FROM BRAIN INJURY BY ALMOST 50% IN A RELATIVELY SMALL BUT IMPORTANT TRIAL
?
?
1: Ann Emerg Med. 2007 Apr;49(4):391-402, 402.e1-2. Epub 2006 Sep 29.
?* Links
ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury.
• Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG.
Department of Emergency Medicine, School of Medicine of Emory University, Atlanta, GA, USA. David.Wright@Emory.edu
STUDY OBJECTIVE: Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering progesterone to patients with acute traumatic brain injury. METHODS: This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale-Extended 30 days postinjury. RESULTS: Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale-Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo. CONCLUSION: In this small study, progesterone caused no discernible harm and showed possible signs of benefit.
PMID: 17011666 [PubMed - indexed for MEDLINE]

[Hopeful]

For anyone who doesn't mind some rather technical reading, try this link: http://content.febsjournal.org/cgi/content/full/269/10/2485

The article explores the role of progestins in growth inhibition/ growth stimulation of bc cells.

Hopeful