possible explanation of why some her+breast cancers are er+ but pr- and what it means

[Lani]

1: Breast Cancer Res Treat. 2006 Sep 28; [Epub ahead of print] Links
Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma.

Tokunaga E,
Oki E,
Kimura Y,
Yamanaka T,
Egashira A,
Nishida K,
Koga T,
Morita M,
Kakeji Y,
Maehara Y.
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan, eriko@surg2.med.kyuhsu-u.ac.jp.
Serine/threonine kinase Akt/PKB is known to regulate divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Akt is activated by a variety of stimuli, through such growth factor receptors as HER2, in phosphoinositide-3-OH kinase (PI3K)-dependent manner. A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt. It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. Therefore, the PI3K/Akt signaling pathway has recently attracted considerable attention as a new target for effective therapeutic strategies. In the present study, we investigated the relationship between Akt activation and either HER2 overexpression or PTEN gene alteration, as well as the PR expression. We analyzed the incidence of LOH at the PTEN locus in 138 breast cancer patients, using our new system for microsatellite analysis, called high-resolution fluorescent microsatellite analysis (HRFMA). We showed Akt activation to significantly correlate with HER2 overexpression or LOH at the PTEN gene locus while inversely correlating with the PR expression. In addition, when LOH at the PTEN gene locus and HER2 overexpression occurred simultaneously, the incidence of Akt activation and reduced PR expression was significant. The association between Akt activation and PR negative expression was observed even in the ER-positive cases. Our results suggest that simultaneous PTEN LOH and HER2 overexpression enhances Akt activation and may thus lead to a negative PR expression.
PMID: 17006756 [PubMed - as supplied by publisher]

[Lani]

1: Clin Cancer Res. 2006 Feb 1;12(3 Pt 2):1013s-1018s. Links
Progesterone receptor loss correlates with human epidermal growth factor receptor 2 overexpression in estrogen receptor-positive breast cancer.

Kim HJ,
Cui X,
Hilsenbeck SG,
Lee AV.
Breast Center, Baylor College of Medicine and the Methodist Hospital, Houston, TX 77030, USA.
Response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. It was originally hypothesized that the ability of PR to predict response to endocrine therapy was due to the fact that PR is an estrogen-regulated gene and that its levels represented a marker of functional ER activity. However, it is now known that loss of PR can occur via multiple mechanisms, many of which do not include ER function, e.g., hypermethylation of the PR promoter and loss of heterozygosity of the PR gene. We have shown that growth factor signaling pathways can directly down-regulate PR levels via the phosphatidylinositol 3'-kinase (PI3K)/Akt/mTOR pathway, and that this can occur independent of ER. For example, overexpression of myr-Akt in MCF-7 cells causes complete loss of PR protein and mRNA but does not reduce ER levels or activity, thus generating ER+/PR- MCF-7 cells. Therefore, the absence of PR may not simply reflect a lack of ER activity but rather may reflect hyperactive cross-talk between ER and growth factor signaling pathways. Consistent with this hypothesis, several recent clinical studies have found that ER+/PR- breast cancers overexpress human epidermal growth factor receptor (HER) 1 and HER2 compared with ER+/PR+ breast cancers. Although HER receptors can lower ER levels, one study showed that loss of PR correlated with high HER2 levels in a multivariate analysis. Furthermore, loss of PTEN, a negative regulator of the PI3K/Akt signaling pathway, has been shown to be associated with specific loss of PR and no change in ER levels. Given the well-recognized resistance of ER+/PR- breast cancer to antiestrogens, more studies are needed to better understand the etiology of ER+/PR- breast cancer, particularly the analysis of other growth factor receptors and their downstream signaling intermediates with respect to PR status.
PMID: 16467118 [PubMed - indexed for MEDLINE]

[Becky]

In your opinion, is it better to at least be ER+ even if PR- than negative for both receptors?

Just wondering your thoughts here.


Thank you in advance

Becky

[Hopeful]

Becky, I have been researching the implications of PR expression in Her2+ bc. In addition to the articles Lani has posted, this is another one that I think has useful information re: PR expression. - Hopeful

Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance.
Breast Center, Baylor College of Medicine, The Methodist Hospital, Houston, TX, USA.

BACKGROUND: Clinical data indicate that estrogen receptor-positive/progesterone receptor-negative (ER+/PR-) breast cancers are less sensitive to tamoxifen than are ER+/PR+ tumors. It has also been reported that tamoxifen may be less effective in tumors that overexpress either HER-2 or HER-1 (epidermal growth factor receptor) and that signaling through these receptors reduces PR expression in experimental models. We hypothesized that ER+/PR- breast tumors are more likely than ER+/PR+ breast tumors to have an aggressive phenotype, to express HER-1 and overexpress HER-2, and are less likely to benefit from tamoxifen adjuvant therapy. METHODS: Clinical and biological features of 31 415 patients with ER+/PR+ tumors were compared with those of 13,404 patients with ER+/PR- tumors. Association between disease-free survival (DFS) and HER-1 and HER-2 status was analyzed in a subset of 11,399 patients receiving adjuvant tamoxifen therapy. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression or Kaplan-Meier analyses, and all statistical tests were two-sided. RESULTS: ER+/PR- tumors were more frequent in older patients, were larger in size, had a higher S-phase fraction, and were more likely to be aneuploid than ER+/PR+ tumors. Furthermore, three times as many ER+/PR- tumors as ER+/PR+ tumors expressed HER-1 (25% versus 8%; P < .001) and 50% more overexpressed HER-2 (21% versus 14%; P < .001). Among all tamoxifen-treated women, recurrence was higher among women with HER-1-expressing tumors than with HER-1-negative tumors (HR = 1.9, 95% CI = 1.0 to 3.5; P = .05); a stronger association between worse DFS and HER-2 overexpression was observed (HR = 2.3, 95% CI = 1.2 to 4.3; P = .006). However, results varied by PR status. Among tamoxifen-treated women with ER+/PR+ tumors, HER-1 or HER-2 status was not associated with worse DFS. Among women with ER+/PR- tumors, however, both HER-1 expression (HR = 2.4, 95% CI = 1.0 to 5.4; P = .036) and HER-2 overexpression (HR = 2.6, 95% CI = 1.1 to 6.0; P = .022) were associated with a higher likelihood of recurrence. CONCLUSIONS: ER+/PR- tumors express higher levels of HER-1 and HER-2 and display more aggressive features than ER+/PR+ tumors. As in laboratory models, lack of PR expression in ER+ tumors may be a surrogate marker of aberrant growth factor signaling that could contribute to the tamoxifen resistance observed in these tumors.

PMID: 16145046 [PubMed - indexed for MEDLINE]

[Lani]

there was one by Arpino showing that in general ER+PR- tumors are resistant to tamoxifen, but sensitive to AIs(no mention of her2 though, if I remember)

'Becky--I am just starting to form an idea of what this might be implying.Unfortunately, neither the North American Trials nor the HERA trials divided out the her2+ER+ patients with respect to PR+ or PR- in the results I have seen.

I am still curious as to what implications this has with respect to the stem cell theory of breast cancer. Is her2 on those cells, is ER+ or PR+ or all all three receptors only present on progenitor cells? Also, are there different gene expression profiles, prognoses and different responses to therapy and natural history (eg time to recurrence) between her2+ er+pr-s and triple positives.

I am still reading and truly haven't formed an opinion yet.

As always I seem to have raised more questions than answers.

Was without internet access for 3 days, so way behind on reading enough to let me formulate an educated opinion yet. It is now 5am here --tried to make up for the 3 days out of touch and got carried away. Sorry I'm not much help for the moment!

[Bev]

B & L, I'm getting ready to nominate you for the Nobel Prize in something. You name it. I'm interested in this thread as my gut feeling as a triple positive is to stay on tamox for a while instead of switching to an AI. I'm having difficulty choosing between uterine cancer and osteoporosis. Don't mean to be dramatic but I l ike to boil things down to their essence which is hard to to with C. BB

[Becky]

Thank you Lani. It is hard to find info on Her2+, ER+ but PR- (as I am).

Hopeful - I have read that article and its a good one. In fact, this is one of the reasons I refused Tamoxifen and got my ovaries removed to take Arimidex (along with Herceptin of which my last one was yesterday).

I think that at least having some hormone positivity is a good thing but not as good as having both. So, for the natural progression of the disease, I am probably "in between" being hormone positive and hormone negative (as my ER is only 50% and my PR is stated as "less than 5%" (which I have always read as negative and my onc states so as well).

Even at ASCO, I searched for some studies on ER+PR- or ER-PR+ but there were only 2 things and all they do is relate it back to the fact that these women should be tested for Her2 as they are probably positive. The one presentation said that when they did their analysis, if these women tested negative for Her2 then they did test positive for Her1 (but this was the only reason they tested for Her1).

Oh well, my whole life I tried to be different so why should my pathology not be!!

Have a nice weekend

Becky

[Hopeful]

Lani, I have read the article from Arpino that you referred to, thanks for mentioning it.

From what I have read, researchers seem to think the triple negatives are in a league of their own - that a form of bc that has no type of endocrine signaling going on is a very basal and different type of cancer. I am not sure if I read the article on this board or found it on my own that talks about the type of cancer being related to the cells from which it arises in the breast. If it wasn't posted here, I can dig it up and provide the link.

The data from the Early Breast Cancer Trialists Collaborative Group poses some provacative questions, IMO. It seems that the prognosticators of ER/PR and nodal status lose their effectiveness the further out from diagnosis you get. I believe that the article I quoted in the DCIS thread is correct, that a number of additional changes take place as the disease progresses which renders these early indicators much less valuable over time.

It fascinates me how complex and truly efficient our bodies are, even when they go about doing the wrong thing. It is unrealistic to expect "fixes" to be as simple as finding an agent that works on only one aspect of a complex, multiple-signaling system with tons of failsafes built in. The approach is analagous to trying to fix the space shuttle with an Allen wrench. On the other hand, the therapies we have today are a whole lot better than leeches!

I always look forward to the research you uncover. Thanks so much for all the time you put into this forum.

Hopeful