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Knowlden J.M.,University of Cardiff | Gee J.M.W.,University of Cardiff | Barrow D.,University of Cardiff | Robertson J.F.,Professorial Unit of Surgery | And 3 more authors.
Breast Cancer Research

Introduction: Recently we reported that insulin receptor substrate 1 (IRS-1), classically an adaptor protein for the insulin-like growth factor type I receptor (IGF-IR), associates with the epidermal growth factor receptor in oestrogen receptor (ER)-positive (ER+) tamoxifen-resistant breast cancer cells. In this study, we examined whether IRS-1 also associates with another erbB receptor family member, erbB3, and what impact this might have on IGF-IR signalling in three ER+ breast cancer cell lines.Methods: Immunoprecipitation and Western blot analysis were utilised to examine the potential association between erbB3 and IRS-1 in MCF-7, T47D and BT-474 cells in the absence and presence of the erbB3/4 ligand heregulin β1 (HRGβ1). Subsequently, the impact of a selective IGF-IR/IR inhibitor 4-anilino-5-bromo-2-[4-(2-hydroxy-3-(N, N-dimethylamino)propoxy)anilino]pyrimidine on this association and HRGβ1 signalling was assessed in these cell lines. Immunohistochemical analysis of a small cohort of ER+ breast cancer patient samples was also performed to determine the potential clinical relevance of this novel interaction.Results: Immunoprecipitation and Western blot analysis revealed an interaction between erbB3 and IRS-1 in MCF-7, T47D and BT-474 cells, with HRGβ1 significantly enhancing this recruitment and promoting IRS-1 phosphorylation at Y612. IRS-1 participates in erbB3 signalling in MCF-7 and T47D cells as IRS-1 knockdown impaired HRGβ1 signalling. Importantly, recruitment of IRS-1 by erbB3 reduced IRS-1 association with IGF-IR in MCF-7 and T47D cells, whilst blockade of IGF-IR-enhanced erbB3-IRS-1 interaction and sensitised both cell lines to HRGβ1, allowing HRGβ1 to override IGF-IR blockade. Consequently, suppression of IRS-1 signalling enhanced the effects of IGF-IR inhibition in these cells. This novel interaction may have clinical relevance, as immunohistochemical analysis of a small ER+ breast tumour series revealed significant positive correlations between phosphorylated IRS-1 Y612 expression and total erbB3, phosphorylated Akt and Ki-67 expression.Conclusions: IRS-1 can be recruited to IGF-IR and erbB3 in ER+ breast cancer cells, and this provides an adaptive resistance mechanism when these receptors are targeted individually. Consequently, cotargeting IGF-IR and either erbB3 or IRS-1 should prove to be a more effective strategy for the treatment of ER+ breast cancer. © 2011 Knowlden et al.; licensee BioMed Central Ltd. Source

Robertson J.F.R.,Professorial Unit of Surgery
European journal of Clinical and Medical Oncology

Fulvestrant, an estradiol analog that binds directly to the estrogen receptor (ER) and anastrozole, an inhibitor of the aromatase enzyme are two antiestrogen agents that are currently used in the endocrine treatment of postmenopausal women with breast cancer. This article reviews the clinical efficacy and safety data for both agents, which led to their approval as monotherapies for the first- or second-line treatment of advanced breast cancer. The use of both agents in combination will also be discussed. Although first approved at a dose of 25o mg, fulvestrant 500 mg has recently been shown to be associated with a clinically meaningful benefit over fulvestrant 250 mg in the second-line setting. While fulvestrant is currently recommended following failure on prior endocrine treatment, suboptimal suppression of the ER at the originally approved 250 mg dose led to further speculation that fulvestrant 500 mg may have increased efficacy in the treatment of advanced disease. Results from the phase III CONFIRM (COmparisoN of Faslodex In Recurrent or Metastatic breast cancer) study show that fulvestrant 500 mg is superior to 250 mg in terms of the primary endpoint of time to progression (TTP). In addition, the phase II Fulvestrant FIRst-Line Study Comparing Endocrine Treatments (FIRST) showed that fulvestrant 500 mg had a similar clinical benefit rate and longer TTP than anastrozole 1 mg as first-line therapy for advanced breast cancer. With their distinct modes of action, both anastrozole and fulvestrant have a critical role to play in the management of hormone receptor-positive advanced breast cancer. Source

Gutteridge E.,Professorial Unit of Surgery | Agrawal A.,Professorial Unit of Surgery | Nicholson R.,University of Cardiff | Cheung K.L.,Professorial Unit of Surgery | And 2 more authors.
International Journal of Cancer

Estrogen receptor (ER)-positive acquired tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell Unes exhibit epidermal growth factor receptor (EGR) expression/signaling and are growth-inhibited by gefitinib (IRESSA). We examined the effect of gefitinib on ER-positive TAM-R and ER-negative hormone-insensitive breast cancer in a Phase Il study. Fifty-four patients with breast cancer [ER-positive/acquired TAM-R (n = 28); ER-negative (n = 26)] received oral gefitinib 500 mg/day. Tumor biopsies were taken pre- (n = 28) and 8 weeks post-treatment (n = 14 matched samples). Gefitinib was well tolerated and the clinical benefit rate (objective response or stable disease >24 weeks) was 33.3% overall (n = 18/54), and 53.6 and 11.5% in ERpositive/TAM-R and ER-negative patients, respectively. Pretreatment ER and progesterone receptor-positivity were associated with response (p < 0.001 and 0.016, respectively) and longer progression-free survival (PFS; p= 0.001 and 0.013, respectively). All patients expressed EGFR, but high pretreatment levels predicted poorer outcome (p = 0.005) and shorter PFS (p = 0.012) with gefitinib. In patients with clinical benefit, reduced Ki67 staining during treatment (p = 0.024) was commonly observed, and those with >10% decline in EGFR phosphorylation demonstrated parallel decreases in ERK1/2 MAPK phosphorylation. Acquired tamoxifen resistance appears in part mediated through EGFR signaling and can be blocked with gefitinib. © 2009 UICC. Source

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