HER2 Support Group Forums - View Single Post

Rich66 · 11-03-2009, 06:24 PM

Int J Oncol. 2007 Feb;30(2):509-20.
Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer.

Osipo C, Meeke K, Cheng D, Weichel A, Bertucci A, Liu H, Jordan VC.
Department of Pathology, Oncology Institute, Cardinal Bernadin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
Tamoxifen resistance is common for estrogen receptor alpha (ERalpha) positive breast cancer. Second-line therapies include aromatase inhibitors or fulvestrant. We have shown previously that fulvestrant reversed 17beta-estradiol-induced tumor regression of tamoxifen-stimulated MCF-7 xenografts (MCF-7TAMLT) treated for >5 years with tamoxifen in athymic mice and paradoxically stimulated growth. We investigated mechanisms responsible for growth by fulvestrant in the presence of physiologic estradiol and therapeutic strategies in vivo. The results demonstrated that only estradiol increased expression of the estrogen-responsive genes, c-myc, igf-1, cathepsin D, and pS2 mRNAs, in MCF-7E2 and MCF-7TAMLT tumors. Tamoxifen or fulvestrant decreased the estradiol-induced increase of these mRNAs in both tumor models. However, tyrosine-phosphorylated HER2/ neu, HER3, phospho-extracellular-regulated kinase-1/2 (ERK-1/2), and phospho-glycogen synthetase kinase 3alpha (GSK3alpha) and beta proteins were increased in MCF-7TAMLT tumors treated with fulvestrant compared to estradiol, control, or tamoxifen. Phospho-HER2/neu interacted with HER3 protein in MCF-7TAMLT tumors. In order to determine whether the functional interaction of HER2/neu with HER3 is critical for growth of fulvestrant-stimulated MCF-7TAMLT tumors, pertuzumab (an antibody that blocks HER2/neu-HER3 interaction) was used in an in vivo xenograft growth assay. Only growth of fulvestrant-treated MCF-7TAMLT xenografts was decreased significantly by 37.2% in response to pertuzumab (P=0.004). Pertuzumab specifically decreased the interaction of HER2/neu protein with HER3 in fulvestrant-stimulated MCF-7TAMLT tumors. These results suggested growth of MCF-7TAMLT tumors by tamoxifen or fulvestrant is potentially independent of ERalpha transcriptional activity as evidenced by lack of induction of four estrogen-responsive genes. The results suggested that growth of MCF-7TAMLT tumors treated with fulvestrant in the presence of physiologic estradiol is in part mediated through enhanced signaling from the HER2/neu-HER3 pathway as pertuzumab partially inhibited growth and the interaction of HER2/neu with HER3 in vivo.

PMID: 17203234 [PubMed - indexed for MEDLINE]

Cancer Biol Ther. 2010 Mar 11;9(5). [Epub ahead of print]
Estrogen receptor-alpha-interacting cytokeratins potentiate the antiestrogenic activity of fulvestrant.

Long X, Fan M, Nephew KP.
Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA; School of Biotechnology, Jiangnan University, Wuxi, China; Zhongnan Hospital, Wuhan University, Wuhan, China.
Fulvestrant (ICI 182, 780) is a selective estrogen receptor downregulator (SERD) and potent antiestrogen. In estrogen receptor alpha positive ERalpha(+) breast cancer, the drug immobilizes ERalpha in the nuclear matrix, inducing receptor polyubiquitination and subsequent degradation via the 26S proteasome. We previously reported that fulvestrant-induced ERalpha degradation depends on the interaction of ERalpha with cytokeratins 8 and 18 (CK8/CK18). Here we further investigate the role of these two cytokeratins in the antagonistic activity of the SERD. Using ER-responsive reporter assays, we demonstrate greater antiestrogenic activity of fulvestrant in CK8/CK18(+) vs. CK8/CK18(-) cancer cells and loss of CK8/CK18 expression was observed in a breast cancer cell model for acquired fulvestrant resistance. In contrast, the presence of CK8/CK18 had no effect on the antiestrogenic activity of 4-hydroxytamoxifen, which was unable to induce an interaction between these CKs and ERalpha. By utilizing the ligand activity inversion ERalpha mutant L540Q to further examine the mechanism of fulvestrant action, we demonstrate that the ERalpha mutant does not interact with CK8/CK18 in the presence of fulvestrant and L540Q is not immobilized to the nuclear matrix after antiestrogen treatment. In transcription assays, fulvestrant displayed agonist activity, stimulating L540Q-mediated gene expression. In addition, fulvestrant did not induce an ERbeta interaction with CK8/CK18 and subsequent ERbeta degradation. Collectively, these results suggest that CK8/18 play an important role in the antiestrogenic action of fulvestrant in breast cancer cells and that these two cytokeratins could serve as prognostic markers for SERD therapy response in breast cancer patients.

PMID: 20061804 [PubMed - as supplied by publisher]

Case Rep Oncol. 2010 Apr 29;3(2):131-136.
Low-Dose Fulvestrant Maintained Long-Term Complete Remission after Poor Response to Previous Endocrine Therapies in a Patient with Advanced Breast Cancer.

Hawle H, Hess D, Mueller A, Thuerlimann B.
Department of Medical Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

FREE TEXT

Abstract

We report a case of long-term (9 years) response to 4th-line endocrine treatment with fulvestrant given for advanced breast cancer after no or poor response to prior endocrine therapies. Complete remission was achieved with full dose and maintained even after dose reduction due to unanticipated intensity of mucosal toxicity. Complete remission was temporarily lost after fulvestrant was tentatively withdrawn (63 months after treatment start), but was re-achieved after renewal of half-dose treatment and last reconfirmed 90 months after treatment start. The pharmacokinetic profile provides evidence to hypothesize a unique sensitivity to fulvestrant in this patient which might explain both: toxicity and extraordinary efficacy.

PMID: 20740185 [PubMed]PMCID: PMC2919988Free PMC Article

Fulvestrant loading, tumor markers,and ongoing trials
Letter to editor COMMUNITY ONCOLOGY ■ November 2007
FULL TEXT

11-03-2009, 06:24 PM	#5
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Fulvestrant+chemo synergy Int J Oncol. 2007 Feb;30(2):509-20. Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer. Osipo C, Meeke K, Cheng D, Weichel A, Bertucci A, Liu H, Jordan VC. Department of Pathology, Oncology Institute, Cardinal Bernadin Cancer Center, Loyola University Medical Center, Maywood, IL, USA. Tamoxifen resistance is common for estrogen receptor alpha (ERalpha) positive breast cancer. Second-line therapies include aromatase inhibitors or fulvestrant. We have shown previously that fulvestrant reversed 17beta-estradiol-induced tumor regression of tamoxifen-stimulated MCF-7 xenografts (MCF-7TAMLT) treated for >5 years with tamoxifen in athymic mice and paradoxically stimulated growth. We investigated mechanisms responsible for growth by fulvestrant in the presence of physiologic estradiol and therapeutic strategies in vivo. The results demonstrated that only estradiol increased expression of the estrogen-responsive genes, c-myc, igf-1, cathepsin D, and pS2 mRNAs, in MCF-7E2 and MCF-7TAMLT tumors. Tamoxifen or fulvestrant decreased the estradiol-induced increase of these mRNAs in both tumor models. However, tyrosine-phosphorylated HER2/ neu, HER3, phospho-extracellular-regulated kinase-1/2 (ERK-1/2), and phospho-glycogen synthetase kinase 3alpha (GSK3alpha) and beta proteins were increased in MCF-7TAMLT tumors treated with fulvestrant compared to estradiol, control, or tamoxifen. Phospho-HER2/neu interacted with HER3 protein in MCF-7TAMLT tumors. In order to determine whether the functional interaction of HER2/neu with HER3 is critical for growth of fulvestrant-stimulated MCF-7TAMLT tumors, pertuzumab (an antibody that blocks HER2/neu-HER3 interaction) was used in an in vivo xenograft growth assay. Only growth of fulvestrant-treated MCF-7TAMLT xenografts was decreased significantly by 37.2% in response to pertuzumab (P=0.004). Pertuzumab specifically decreased the interaction of HER2/neu protein with HER3 in fulvestrant-stimulated MCF-7TAMLT tumors. These results suggested growth of MCF-7TAMLT tumors by tamoxifen or fulvestrant is potentially independent of ERalpha transcriptional activity as evidenced by lack of induction of four estrogen-responsive genes. The results suggested that growth of MCF-7TAMLT tumors treated with fulvestrant in the presence of physiologic estradiol is in part mediated through enhanced signaling from the HER2/neu-HER3 pathway as pertuzumab partially inhibited growth and the interaction of HER2/neu with HER3 in vivo. PMID: 17203234 [PubMed - indexed for MEDLINE] Cancer Biol Ther. 2010 Mar 11;9(5). [Epub ahead of print] Estrogen receptor-alpha-interacting cytokeratins potentiate the antiestrogenic activity of fulvestrant. Long X, Fan M, Nephew KP. Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA; School of Biotechnology, Jiangnan University, Wuxi, China; Zhongnan Hospital, Wuhan University, Wuhan, China. Fulvestrant (ICI 182, 780) is a selective estrogen receptor downregulator (SERD) and potent antiestrogen. In estrogen receptor alpha positive ERalpha(+) breast cancer, the drug immobilizes ERalpha in the nuclear matrix, inducing receptor polyubiquitination and subsequent degradation via the 26S proteasome. We previously reported that fulvestrant-induced ERalpha degradation depends on the interaction of ERalpha with cytokeratins 8 and 18 (CK8/CK18). Here we further investigate the role of these two cytokeratins in the antagonistic activity of the SERD. Using ER-responsive reporter assays, we demonstrate greater antiestrogenic activity of fulvestrant in CK8/CK18(+) vs. CK8/CK18(-) cancer cells and loss of CK8/CK18 expression was observed in a breast cancer cell model for acquired fulvestrant resistance. In contrast, the presence of CK8/CK18 had no effect on the antiestrogenic activity of 4-hydroxytamoxifen, which was unable to induce an interaction between these CKs and ERalpha. By utilizing the ligand activity inversion ERalpha mutant L540Q to further examine the mechanism of fulvestrant action, we demonstrate that the ERalpha mutant does not interact with CK8/CK18 in the presence of fulvestrant and L540Q is not immobilized to the nuclear matrix after antiestrogen treatment. In transcription assays, fulvestrant displayed agonist activity, stimulating L540Q-mediated gene expression. In addition, fulvestrant did not induce an ERbeta interaction with CK8/CK18 and subsequent ERbeta degradation. Collectively, these results suggest that CK8/18 play an important role in the antiestrogenic action of fulvestrant in breast cancer cells and that these two cytokeratins could serve as prognostic markers for SERD therapy response in breast cancer patients. PMID: 20061804 [PubMed - as supplied by publisher] Case Rep Oncol. 2010 Apr 29;3(2):131-136. Low-Dose Fulvestrant Maintained Long-Term Complete Remission after Poor Response to Previous Endocrine Therapies in a Patient with Advanced Breast Cancer. Hawle H, Hess D, Mueller A, Thuerlimann B. Department of Medical Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. FREE TEXT Abstract We report a case of long-term (9 years) response to 4th-line endocrine treatment with fulvestrant given for advanced breast cancer after no or poor response to prior endocrine therapies. Complete remission was achieved with full dose and maintained even after dose reduction due to unanticipated intensity of mucosal toxicity. Complete remission was temporarily lost after fulvestrant was tentatively withdrawn (63 months after treatment start), but was re-achieved after renewal of half-dose treatment and last reconfirmed 90 months after treatment start. The pharmacokinetic profile provides evidence to hypothesize a unique sensitivity to fulvestrant in this patient which might explain both: toxicity and extraordinary efficacy. PMID: 20740185 [PubMed]PMCID: PMC2919988Free PMC Article Fulvestrant loading, tumor markers,and ongoing trials Letter to editor COMMUNITY ONCOLOGY ■ November 2007 FULL TEXT __________________ Mom's treatment history (link)