[al from Canada]

Sorry for taking so long but we have not forgotten about you but this a very conplex thing and will get even more complex as we add other mokecular targets to our profiling abd try to match these up with other downstream interactions and the appropriate targetted therapies. This topic is also very close to where my personal theories on ERGF X-talk / PI3K / PTEN / Insulin resistance / heat hock proteins / VEGF interactions relate to putting the brakes on the proliferation of this horrible disease. There is no magic bullet that will ever be found as a curative measure because clearly, there are too many pathways, escape mechanisms and individual differences that impact the the outcome of any one's therapy. There are common factors within HER2 cancers that offer a glimmer of hope and treatment combinations that haven't been explored.
I believe one route, and I've been hammering away at this of months now, is the use of Hercpetin + a variety of HER1 inhibitors + other tagetted therapies that have a compounded effect on blocking / activating other related pathways to cancer proliferation.

Here is one and altough it refers to prostate Ca, there are undeniable similarities with BC.

C Festuccia1, P Muzi1, D Millimaggi1, L Biordi1, G L Gravina2, S Speca1, A Angelucci2, V Dolo1, C Vicentini2 and M Bologna1,3


1 Departments of Experimental Medicine,
2 Surgery and
3 Basic and Applied Biology, University of L’Aquila, Via Vetoio, Coppito-2, 67100 L’Aquila, Italy


(Requests for offprints should be addressed to C Festuccia; Email: festucci@univaq.it ) To date, no effective therapeutic treatment allows abrogation of the progression of prostate cancer (PCa) to more invasive forms. One of the major targets for the therapy in PCa can be epidermal growth factor receptor (EGFR), which signals via the phosphoinositide 3'-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways, among others. Despite multiple reports of overexpression in PCa, the reliance on activated EGFR and its downstream signalling to the PI3K and/or MAPK/extracellular signal-regulated kinase (ERK) pathways has not been fully elucidated. We reported that the EGFR-selective tyrosine kinase inhibitor gefitinib (ZD1839; Iressa) is able to induce growth inhibition, G1 arrest and apoptosis in PCa cells and that its effectiveness is associated primarily with phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression (and thus Akt activity). In fact PTEN-negative PCa cells are slowly sensitive to gefitinib treatment, because this molecule is unable to downregulate PI3K/Akt activity. PI3K inhibition, by LY294002 or after PTEN transfection, restores EGFR-stimulated Akt signalling and sensitizes the cells to pro-apoptotic action of gefitinib. The MAPK pathway seems to be involved primarily on cell-growth modulation because dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition (both not cell apoptosis) in PTEN-positive PCa cells and reduced EGF-mediated growth in PTEN-negative cells. Thus the effectiveness of gefitinib requires growth factor receptor-stimulated PI3K/Akt and MAPK signalling to be intact and functional. The loss of the PTEN activity leads to uncoupling of this signalling pathway, determining a partial gefitinib resistance. Moreover, gefitinib sensitivity may be maintained in these cells through its inhibitory potential in MAPK/ERK pathway activity, modulating proliferative EGFR-triggered events. Therefore, our data suggest that the inhibition of EGFR signalling can result in a significant growth reduction and in increased apoptosis in EGFR-overexpressing PCa cells with different modalities, which are regulated by PTEN status, and this may have relevance in the clinical setting of PCa.

In this article, PTEN is also associated with VEGF and what is also interesting is that the % of PTEN loss is the same as HER2 overexpression.

Loss of PTEN expression has been associated with advanced stages of tumor. Tumor angiogenesis is involved in tumor progression. In breast cancer, a high frequency of mutations of the PTEN locus has been reported. However, the prognostic importance of PTEN expression and its correlation with angiogenesis in breast cancer have not been well established. Formalin-fixed, paraffin-embedded tissues from 99 women with a primary diagnosis of invasive ductal carcinoma were evaluated for PTEN expression by immunohistochemical methods. The microvessel density (MVD) was also studied by immunohistochemical labeling of endothelial cells with CD34 antibody. Computerized image analysis was used to evaluate MVD. Reduced PTEN expression was seen in 27.3% of invasive ductal carcinoma. The MVD ranged from 22.0 to 197.0, with a median value of 58.5 (65.4 +/- 27.9). Reduced PTEN expression correlated with lymph node status (P < 0.01), tumor grade (P < 0.05), and tumor-node-metastasis (TNM) stage (P < 0.05). There was a statistically significant correlation between reduced PTEN expression and increased MVD (P < 0.05). The mean MVD was higher in reduced PTEN-expressive tumors, irrespective of stage, compared with normal PTEN-expressive tumors with the same stage. On multivariate analysis, only TNM stage and reduced PTEN expression correlated with survival. Our results suggest that reduced PTEN expression may be an independent prognostic indicator in patients with invasive ductal carcinoma. PTEN loss may be associated with increased tumor angiogenesis.

There is much more on this and many other complicating factors but you have to start somewhere.

Take care,
Al