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Re: Her2+ PR+ bc patients may benefit from anti-progestin therapy
Laurel, I am neither a scientist nor a doctor, but I will do my best.
The researchers determined that there was very little overlap between normal progestin regulated genes in normal breast tissue and cancerous breast tissue. They think that the genetic signaling may be altered very early in the course of breast cancer. They were then able to isolate several groups of genes that were regulated by progestin in conjunction with other receptors. In particular, they identified a meta-progestin gene signature called SUMO. If SUMO was present, a signaling network was created that allowed cells to multiply out of control in response to exposure to progestin. If SUMO was not present, the signaling pathway in the cells was inactive, and they did not respond to progestin. There was a very strong affinity between progestin and a group of genes associated with Her2+ promoting genes:
"Remarkably, five distinct ERBB2-positive breast cancer concepts (two from cell lines and three from tumor cohorts) were independently associated with this LD PR-gene signature. Thus, genes specifically upregulated in the presence of progestin in cells expressing SUMO-deficient PR are among the same genes highly over-expressed (top 5-10%) in ERBB2-postive breast cancers. Notably, the LI 92-gene signature was also significantly associated with at last one ERBB2-positive concept. These data indicate that both ligand-dependent and independent unique PR-regulated gene sets are significantly upregulated in protein-kinase-driven tumors, including those known to be ERBB2-positive."
As part of their experiment, they isolated these gene groups and treated the cells with doxorubicin, which is adriamycin chemotherapy. The cells which were stimulated by progestin not only weren't killed by the chemotherapy, they doubled in number as a result of the treatment:
"PR-null cells and cells stably expressing either WT or KR PR [WT is one of the cell groups they identified that is associated with progestin and HER2+ - Hopeful]were plated in complete media, serum starved and treated with R5020 [R5020=progestin - Hopeful], with or without doxorubicin. Again, we observed significantly increased cell viability in progestin treated cells expressing SUMO-deficient KR PR. Interestingly, when these cells were challenged with cytotoxic concenterations of doxorubicin, their viability was doubled relative to cells expressing WT PR. These data suggest that SUMO-deificient PRs are important mediators of increased cell proliferation and pro-survival signaling; cells expressing modified PRs undergo biological processes consistent with their associated gene profile."
The researchers then tested an anti-progestin endocrine therapy on the Her2+ PR+ cells with excellent results:
"Luminal breast tumors are primarily SR [SR=steriod receptor - Hopeful] positive, but approximately 7% of luminal A and 20% of luminal B tumors are Her2-enriched. We therefore tested the PR- and MAPK-dependent regulation of selected genes co-associated with ERBB2 overexpression and SUMO sensitivity (above) in Her2-amplified but SR-positive BT-474 breast cancer cells that contain constitutively activated MAPKs. Antiprogestin treatment dramatically inhibits BT-474 tumor growth in xenograft models and significantly blocks BT-474 cell proliferatio in MTT assays conducted over six days in vitro; similar results were obtained with the MEK inhibitor."
Their study of SUMO lead to more questions, as they found that SUMO could either promote or repress different cancer stimulating genes in different cell lines.
They end their discussion with the following remarks:
"Notably, as SR+ luminal A-type tumors progress towards a more aggressive growth factor-high luminal B-type phenotype, SR expression begins to decline, starting with PR loss. These poor prognosis luminal B-type tumors are often clinically characterized as ER+/PR-low or null and are more likely to become endocrine resistant. We showed previously that SUMOylated phospho-PR function as hyperactive receptors but also turnover rapidly via the ubiquitin-proteasome pathway. In fact, when PR-dependent transcription peaks, as measured by RT-qPCR of endogenous gene readouts (via mRNA levels) or using reporter genes, PR protein levels are virtually undetectable. This finding raises the important question of whether PR is also hyperactive in a subset of breast tumors that are clinically defined as PR-low or null (i.e. as generally measured by methods of total protein detection in clinical settings.) Interestingly, breast tumors are capable of de novo progestrone synthesis, a process mediated by growth factor-dependent signaling. Tumor-cell (local) production of progesterone may contribute to sustained PR action (i.e. at ligand-dependent genes) in more aggressive ER+/PR+ tumors.
Suprisingly, herein we found that breast cancer cells expressing SUMOylated phospho-PR drive the expression of cell proliferation genes, many directly involved in the positive regulation of the ERBB/MAPK signaling pathway, thus setting up a type of "feed-forward" vicious cylce that is clearly associated with tumor progression. Our data suggest that phospho-PR may act as a driver of this transition (i.e., tumor progession towards the gain of growth-factor driven pathways that can proceed SR loss) as indicated by significant similarity to our uniquely defined PR signatures. Our key findings are supported by available clinical data from the Women's Health Initiative and the Million Women's Study showing that breast tumors that arose in women taking a progestin as part of HRT were more frequent, larger, and of higher grade relative to control groups. Remarklably, a recent analysis of these data demonstrated that estrogen-only HRT may actually protect women from invasive breast cancer. Taken together with the work of others, our data support the concept that targeting PR action in breast cancer patients may be highly beneficial, especially for patients that become SERM resistant. Of note, roughly 40% of patients will initially fail or eventually develop resistance to endocrine therapies aimed solely at targeting estrogen action; this represents a large and underserved population."
My take aways from the above quoted material:
1. Progestrone is a bad actor in bc.
2. The level of positivity for the PR steroid receptor in the tumor does not necessarily correlate with PR signaling activity in the tumor.
3. Those tumors that are affected by the meta-progestin signature, SUMO, have a worse prognosis.
4. Breast tumors are capable of synthesizing their own progesterone, which means that external exposure to progesterone is not required for progesterone stimulation of the cancer cells to occur.
5. Some cells that are affected by SUMO are identified with a particular strain of Her2+ breast cancer cells.
6. As breast cancer progresses, more cells lose their ER+/PR+ expression, and can also become less receptive to Tamoxifen.
7. For patients that fall into one or both of those groups described in nos. 5 & 6 above, anti-progestin therapy was shown to be effective in these laboratory studies.
That's all I got.
Hopeful
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