for Jean and others worried about antiendrocrine therapy resistance
Endocr Relat Cancer. 2006 Dec;13 Suppl 1:S77-88.
Deciphering antihormone-induced compensatory mechanisms in breast cancer and their therapeutic implications.
Gee JM,
Shaw VE,
Hiscox SE,
McClelland RA,
Rushmere NK,
Nicholson RI.
Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Redwood Building, Cardiff University, Cardiff, Wales, UK.
Breast cancer inhibition by antihormones is rarely complete, and our studies using responsive models reveal the remarkable flexibility of breast cancer cells in recruiting alternative signalling to limit maximal anti-tumour effects of oestrogen receptor alpha (ER) blockade. The recruited mechanism involves antihormone-induced expression of oestrogen-repressed signalling genes. For example, epidermal growth factor receptor gene (EGFR) is induced by antioestrogens and maintains residual kinase and ER phosphorylation, cell survival genes, and thereby allows incomplete antihormone response and emergence of resistance. Microarrays are revealing the breadth of antihormone-induced genes that may attenuate growth inhibition, including NFkappaB, Bag1, 14-3-3zeta and tyrosine kinases, such as HER2 and Lyn. Three concepts are emerging: first, some genes are induced exclusively by antioestrogens, while others extend to oestrogen deprivation; secondly, some are transiently induced, while others persist into resistance; finally, some confer additional adverse features when tumour cells are in an appropriate context. Among the latter is CD59 whose antioestrogen induction may permit evasion of immune surveillance in vivo. Also, induction of pro-invasive genes (including NFkappaB, RhoE and delta-catenin) may underlie our findings that antioestrogens can markedly stimulate migratory behaviour when tumour intercellular contacts are compromised. Based on our promising studies selectively inhibiting EGFR (gefitinib), NFkappaB (parthenolide) or CD59 (neutralising antibody) together with antioestrogens, we propose that co-targeting strategies could markedly improve anti-tumour activity (notably enhancing cell kill) during the antihormone-responsive phase. Furthermore, subverting those induced signalling genes that are retained into resistance (e.g. EGFR, NFkappaB, HER2) may prove valuable in this state. Alongside future deciphering and targeting of genes underlying antioestrogen-promoted invasiveness, embracing of intelligent combination strategies could significantly extend patient survival.
PMID: 17259561 [PubMed -
This implies that in the future they may find less recurrences if they combine targetted therapies against various paths the cancer uses to escape the antihormonal with the antihormonal, perhaps for extended periods. If not knowing this, or the worry generated by knowing this may be the case annoys you, be aware that I try to post a yield warning sign next to articles that do not provide a positive answer for something that can be a source of worry.
There will always be things to worry about. But if one follows the developments it may be possible to be one of the first to try out a treatment developed to solve the problem
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