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

[Lani]

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]

I think this one will need subtitles.

[sarah]

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

[Ellie F]

And me!
Ellie

[Becky]

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]

Thank you Becky for the explanation.
Ellie

[Lani]

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]

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:

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]

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]

I am confused---

I am HER2+ and ER-

what is this saying?

[Laurel]

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]

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]

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]

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!

[Rich66]

Yeah..well...it's quite clear no one would take any of this stuff if it weren't a relative benefit. The benefit being staying alive..chemo brain and all. So..yeah..leave my macho estrogen alone..unless it's killing me.

Hutchi, all you need is one of these:

[Laurel]

Oh! I want a propeller hat, too! Funny how one thing seems to beget a thousand other questions and contingencies. I still say: if cancer is so damned smart, how come it kills its host? Huh??? Oh yeah, take that cancer!

[TSund]

Rich,

Could you send me to the studies or articles ( or a thread here?) that reference what you said about fulvestrant being possibly better for HER2 cancer?

THanks much!

Terri

[Rich66]

Since Fulvestrant seems to work after other antiestrogens/AIs cease working, could be prudent to save it for last. I will mention the makers of Tamoxitest had a poster at SABC 09 suggesting that in definite Her2 positives, Tamoxifen might not be a good choice. Not sure yet if anyone else is backing this up.

From Fulvestrant + chemo thread:

Ann Oncol. 2009 Oct 29. [Epub ahead of print]
Activity of fulvestrant in HER2-overexpressing advanced breast cancer.
Robertson JF, Steger GG, Neven P, Barni S, Gieseking F, Nolè F, Pritchard KI, O'Malley FP, Simon SD, Kaufman B, Petruzelka L.
Professorial Unit of Surgery, Division of Breast Surgery, University of Nottingham, Nottingham City Hospital, Nottingham, UK.
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpression increases the aggressiveness of breast cancer cells resulting in poorer prognosis. Patients with HER2-positive disease are less responsive to endocrine therapies. Trastuzumab monotherapy results in objective responses in only approximately 15% of patients. Fulvestrant retains activity in cells overexpressing HER2 that are resistant to other endocrine treatments. This retrospective study evaluated response to fulvestrant treatment among HER2-positive patients with advanced breast cancer (ABC). PATIENTS AND METHODS: Clinical experience data from 10 treatment centres were pooled. Postmenopausal patients with predominantly hormone receptor-positive and HER2-positive disease were included. Clinical benefit (CB) was defined as the proportion of patients achieving a response to treatment (partial or complete) or stable disease lasting >/=6 months. RESULTS: Data for 102 patients were analysed. Fulvestrant resulted in an overall CB rate of 42% (43/101) in HER2-positive patients and 40% (25/63) in patients with visceral disease. Median duration of treatment was 14.5 months (range 6-44 months). Fulvestrant showed activity up to the fourth line of endocrine therapy and up to the seventh line of overall therapy. CONCLUSIONS: Results indicate that fulvestrant may be a suitable treatment option in extensively pre-treated patients with HER2-positive, hormone receptor-positive ABC. Further exploration of its use in this patient population is warranted.
PMID: 19875750

From ER/Her2 crosstalk thread:

SABC 2009
[708] Different Mechanisms for Acquired Resistance to Trastuzumab and Lapatinib in HER2 Positive Breast Cancers: Role of ER and HER2 Reactivation.

Wang Y-C, Hennessy B, McAninch Ward R, Rimawi M, Huang C, Mills GB, Osborne CK, Schiff R Baylor College of Medicine, Houston, TX; M.D. Anderson, Houston, TX



About 25% of human breast cancers are amplified for HER2 with half of these tumors also expressing estrogen receptor (ER). Therapies targeting HER2 are very effective in the metastatic and the adjuvant settings, especially, although de novo or acquired resistance are still major problems. Trastuzumab (T) and lapatinib (L) are approved drugs now used in the clinic for treatment of HER2+ tumors. Data suggest that T works primarily by blocking signals generated by HER2 homodimers, while L is a small molecule tyrosine kinase inhibitor that more completely blocks the pathway by inhibiting HER1 in addition to HER2. In the clinic, these drugs demonstrate incomplete cross-resistance since L is active in some patients with T-resistant tumors. However, the mechanisms for this resistance have not been clarified.
To investigate the mechanisms for acquired resistance, we developed a panel of HER2+ cell lines resistant to T, L, and L+T by long-term exposure to increasing drug concentration in vitro. Two of these lines, BT474 and UACC812, are amplified for HER2 and also express ER, and they, together with subclones resistant to L, T, and L+T, were used to better understand potential resistance mechanisms. Western blot analysis of the parental BT474 and its resistant subclones showed that subclones resistant to T had reactivated the HER2 signaling pathway, while subclones resistant to L or L+T in which the HER receptor layer was more completely inhibited showed continued complete blockade of the HER2 pathway at the receptor layer but high levels of ER activity and phosphorylated-AKT. L, but not L+T, subclones after more prolonged time in culture did reactivate the HER pathway. UACC812 resistant cells were similar to BT474: T-resistant clones showed evidence of reactivation of HER signaling while L and L+T resistant clones showed enhanced ER activity. These cells showed no reactivation of HER signaling even after prolonged exposure in vitro. Consistent with these data, both BT474 and UACC812 T-resistant clones were still sensitive to and cell proliferation was inhibited by L. L-resistant clones, however, were also resistant to T. The potent anti-estrogen fulvestrant (F) was used to evaluate the role of ER in these resistant clones. T-resistant clones from both parental lines were resistant to F, indicating that ER had no role in resistance. In contrast, L and L+T-resistant clones, but not parental cells, were extremely sensitive to F with significant inhibition of cell proliferation in vitro.
These data demonstrate that only partial inhibition of the HER2 pathway in breast cancer cells by T can be overcome by activating other components of the HER pathway. Resistance to more complete HER2 blockade with L or L+T requires reactivation of a redundant cell survival pathway, in this case ER, which is upregulated by HER2 blockade. Optimal therapy in those tumors may require both ER and HER2-targeted therapy.

Saturday, December 12, 2009 7:00 AM


Note that a higher dose (500) than previous (250) is considered more effective now.

[Lani]

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

[Adriana Mangus]

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