getting her2+ER- bc to reexpress ER & consequences more complicated than thought

Lani · 01-01-2010, 04:10 PM

Int J Oncol. 2010 Feb;36(2):451-8.
Expression of estrogen receptor alpha with a Tet-off adenoviral system induces G0/G1 cell cycle arrest in SKBr3 breast cancer cells.
Peng J, Jordan VC.

Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Endocrine therapies targeting estrogen action are pivotal for the prevention and treatment of ER-positive breast cancers. Previous studies sought to recreate hormone responsiveness by the stable expression of ERalpha in the ER-negative MDA-MB-231 breast cancer cells. Paradoxically, estrogen inhibits breast cancer cell growth when an exogenous ERalpha is expressed. In this study, we have built on previous studies by developing a Tet-off adenoviral system to express ERalpha in the ER-negative SKBr3 breast cancer cells that over-express both EGFR and HER2. This system efficiently delivers ERalpha and the expression level of ERalpha is controlled by doxycycline in a concentration-dependent manner. The growth of SKBr3 was inhibited by ERalpha expression and further inhibited in the presence of 1 nM 17beta-estradiol. SKBr3 cells were arrested at G0/G1 cell cycle upon ERalpha expression, which corresponded to an increase of p21Cip1/Waf1, hypo-phosphorylation of pRb and decrease of E2F1. Estrogen also reduced EGFR and HER2 expression in SKBr3 cells after ERalpha was expressed. Given that estrogen-induced increase of p21Cip1/Waf1 and decrease of E2F1 was also observed in MDA-MB-231 cells stably transfected with ERalpha, our results suggest that a common pathway might be shared by different breast cancer cell lines whose growth is suppressed by ectopic ERalpha and estrogen.

PMID: 20043081

Rich66 · 01-01-2010, 05:13 PM

I think this one will need subtitles.

sarah · 01-02-2010, 02:23 AM

love the way you put that Rich! It's Greek to me also.

Ellie F · 01-02-2010, 06:13 AM

And me!
Ellie

Becky · 01-02-2010, 08:02 AM

This is what I think this says. There are 2 bc cell lines used in this study that are ER negative lines - one of these lines is Her2+ and EGFR (aka Her1+). Using a virus, they put in a genetic component that made the cell line also ER+ (ERAlpha - this is the main ER+ marker there is also an ERBeta which isn't as "strong"). When the ER component was inserted, it immediately downgraded the cancer, slowed its growth and it began to not express the Her family as much. This happened because of certain pathways that ER+ cancer uses (all the other gobbldee goop).

Ellie F · 01-02-2010, 10:35 AM

Thank you Becky for the explanation.
Ellie

Lani · 01-02-2010, 11:00 AM

the reason I said it was more complicated than previously thought--many of you who are her2+er- have wished to be transformed into her2+er+ by treatments restoring ER expression--in your posts you stated "then I could be treated with AIs AND herceptin and have more treatment options"

As it turns out, when ER was reintroduced in this study, estrogen itself was what inhibited growth, NOT antiestrogens

I refer to the following sentences:

The growth of SKBr3(a her2+er cell line) was inhibited by ERalpha expression and further inhibited in the presence of 1 nM 17beta-estradiol.

Paradoxically, estrogen inhibits breast cancer cell growth when an exogenous ERalpha is expressed

Estrogen also reduced EGFR and HER2 expression in SKBr3 cells after ERalpha was expressed.

How ER(alpha and beta) and her2 interact is complicated and is still being worked out.

Rich66 · 01-02-2010, 11:22 AM

The idea of estrogen inhibiting ER pos cancers has come up before...to the point that some view alternating inhibition and addition of estrogen as way to control ER+ cancer.

One interesting TAM related example is here:

Quote:

there are distinct phases of resistance to tamoxifen that correlate with time of treatment and expression of HER2/neu mRNA. In the treatment phase, 17beta-estradiol (E2) stimulated growth, while TAM inhibited growth of MCF-7 tumors (MCF-7E2). The withdrawal of treatment, mimicking the use of an AI, completely prevented growth. In Phase I resistance, the tumors (MCF-7TAMST) were growth-stimulated by either E2 or TAM, but inhibited by no treatment, fulvestrant, or E2 + fulvestrant. Phase II-resistant tumors (MCF-7TAMLT) were treated for more than 5 years and growth-stimulated by TAM. However, no treatment, fulvestrant, or E2 completely inhibited growth. Interestingly, the few tumors (MCF-7TAMLT) that survived in response to E2 were robustly re-stimulated by E2 after transplantation into new generations of athymic mice. These E2-stimulated tumors (MCF-7TAME) were inhibited by TAM in a dose-dependent similar to their parental tumors (MCF-7E2). In addition, the MCF-7TAME tumors were inhibited by either no treatment or fulvestrant. HER2/neu and HER3 mRNAs were over-expressed in TAM-stimulated MCF-7TAMLT tumors and remained high in E2-stimulated MCF-7TAME tumors. The data indicate that complete reversal of resistance to TAM can be achieved with the use of low dose E2 therapy. Also, these data suggest that over-expression of HER2/neu alone is insufficient to predict resistance to TAM. Based on the results, we suggest using an alternating treatment regimen, cycling antiestrogen with estrogen therapy to avoid drug-resistance.

Issues of er/her2 crosstalk here

Hopeful · 01-02-2010, 02:58 PM

Earlier in the week, I posted a review article that discussed the capacity of Estrogen to both promote and inhibit proliferation under different conditions: http://her2support.org/vbulletin/sho...rid=1173<br />

Hopeful

Cal-Gal · 01-02-2010, 04:56 PM

I am confused---

I am HER2+ and ER-

what is this saying?

Laurel · 01-02-2010, 06:40 PM

I'm watching the final episode in the Dr. Who series with David Tennant as the Doctor on BBC America. I'm too depressed about having a new Doctor to care about Estrogen and all its nuances! LOL! I mean, there are real worries in life!

Did think when I read Lani's post, "Oh, goody! Toss out the stinkin' Femara!"

Rich66 · 01-02-2010, 07:20 PM

Laurel,
Not sure this manipulation of Her2+/Er- proves that naturally ER+/Her2+ cancers never respond to estrogen inhibition.
But..it does seem to be vague on clinical implications.
From what I've read, Fulvestrant may be the top "E-hibitor" for Her2+. But I think Femara is thought to reduce estrogen the most in terms of aromatase inhibitors. Fulvestrant seems to have the best chance of working after other e-hibitors are spent so it might make sense to use Femara first. Alternating low dose e to resensitize might extend use of all the e-hibitors.

hutchibk · 01-02-2010, 08:22 PM

Let me just say for the record, akljoeiuoiruaeoihtjsajg,mvckjvo;slkdaknakjcxhvkj.

Me thinks we are now in territory that is so far over my head that I need to be on the space shuttle to try and grasp it.

Lani · 01-02-2010, 08:35 PM

Aromatase is only one of several enzymes that makes estrogen in postmenopausal women--AIs only block this enzyme and not the rest.

Fulvestrant degrades the actual receptor so that even if estrogen is around there is nothing to respond to it.

The problem is that estrogen has multiple effects all over the body and once the ER is degraded by Fulvestrant it never comes back. That is fine in areas of the body where the cells are constantly being replaced ie, once fulvestrant is blocked the new cells will have ERs, but estrogen is very important in the brain--tell me about it! (even in males, Rich66!) and noone seems to know for sure if fulvestrant crosses the blood-brain barrier.

Lots still to find out and that isn't even including under what circumstances estrogen promotes bc growth and under what circumstances it inhibits it!

Adriana Mangus · 01-05-2010, 12:58 AM

Someone please pick me up on that little funny propeller!!! Me too, no entiendo.....way over my head..

TSund · 01-05-2010, 09:16 AM

Has there been any studies for fulvestrant or exemestane (Aromasin) vs the non-steroidal AI's for non-metastatic HER2 breast cancer?

I"m also not clear on where fulvestrant fits into the picure vs tamoxifen, aromasin/femara, and aromasin, particularly with non-metastatic cancer. I think it was developed as a treatment for metastatic cancer, but is now branching into locally advanced cancer, etc?

Thanks

TRS

Lani · 01-06-2010, 02:49 AM

as far as I know fulvestrant only being used for metastatic bc (may be some trials going on for adjuvant, but I haven't heard them reported)

Hopeful · 01-06-2010, 12:56 PM

Quote:

also presented at SABCS if tumor is her2 AND her3 positive it tends to be resistant to all antihormonal treatments.

The following post in the Articles Forum contains a discussion of the presentation referenced by Lani above.

http://her2support.org/vbulletin/sho...eferrerid=1173

Hopeful

Lani · 01-07-2010, 01:07 AM

Thanks Hopeful. When I heard the talk I heard endocrine treatment insensitive (not partially insensitive). I perked up to be sure I heard right. Will try to see if that talk ends up online to listen again.

Hopeful · 01-07-2010, 07:32 AM

Lani,

I have a few questions about the trial that perhaps you can answer. I am including a link to the abstract from SABCS that accompanies the main subject of the article in the articles forum: http://www.abstracts2view.com/sabcs0...=SABCS09L_1839

Am I correct in that this was a European study? The results portion of the abstract says, "Between 2001 and January 2006, 9775 women were randomized to TEAM. In total, 99% of patients were ER+ and/or PgR+, 50% were node-negative, 44% underwent mastectomy, 68% received radiotherapy, and 36% received chemotherapy." There is no mention here of Herceptin. Do you know if any of the trial participants received Herceptin? I am thinking given the time frame and location the participants were drawn from, that they most likely did not.

Do I understand that those who were resistant are both Her2+ and Her3+, or was it either/or? When it is written with the slash, as it is in the article I posted, I am not sure how to interpret it.

Thanks for any light you can shed.

Hopeful