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Endocrine therapy is the treatment of choice in hormone receptor-positive breast cancer. However, the effectiveness of these agents is limited by the development of drug resistance, ultimately leading to disease progression and patient mortality. Cell models of endocrine resistance have demonstrated a role for altered growth factor signalling in the development of an endocrine insensitive phenotype. Significantly, recent studies have revealed that the acquisition of endocrine resistance in breast cancer is also accompanied by the development of an adverse cellular phenotype, with resistant cells exhibiting altered adhesive interactions, enhanced migratory and invasive behaviour, and a capacity to induce angiogenic responses in endothelium. Since invasion and metastasis of cancer cells is a major cause of mortality in cancer patients, elucidation of molecular mechanisms underlying the adverse cellular features that accompany acquired endocrine resistance and their subsequent targeting may provide a means of limiting the progression of such tumours in vivo.

Antihormones are of substantial benefit in treating oestrogen receptor-α positive (ER+) breast cancer. However, their anti-tumour effect is limited by emergence of resistance. Our in vitro studies are highlighting a new underlying concept: that antihormones are not passive bystanders but alongside growth inhibitory effects promote adverse compensatory mechanisms within tumour cells. These mechanisms involve drug-induction of signalling elements normally suppressed by oestrogen (E2)-occupied E R˜ While best exemplified by the tyrosine kinases epidermal growth factor receptor and HER2, microarrays reveal the true diversity of the induced signalling kinases, where their potential to promote resistance is exacerbated under paracrine conditions. Such drug-induced events permit initial ER+ breast cancer cell survival, allow development and maintenance of resistance, and also promote gain of invasiveness under conditions of poor intercellular contact. In addition, prolonged antihormonal exposure is associated with epigenetic silencing of classical E2-induced tumour suppressors, an event which further contributes to resistance. Based on proof of principle experiments targeting induced signalling events alongside antihormones or restoring E2-induced suppressor genes through DNA methylation inhibitor-containing strategies, it is our belief that continued deciphering of these mechanisms will reveal improved treatments for breast cancer.

Despite the initial success of endocrine therapies, a significant proportion of women will acquire resistance to such treatments. Furthermore, clinical relapse during anti-hormonal therapy has been linked to tumours that have gained an aggressive phenotype and enhanced metastatic capacity and is frequently associated with a poorer outlook for the patient. Recently, we have demonstrated that the acquisition of an endocrine resistant state in breast cancer cells is accompanied by a profound increase in invasive capacity. Tumour cell invasion is fundamental to the subsequent development of metastasis, the most significant factor that affects the survival of patients with cancer. Despite this, past therapeutic approaches have paid relatively little attention to these important issues; thus a greater understanding of this process will lead to the identification of potential targets for anti-invasive intervention for such patients. To this end, we are currently addressing potential mechanisms which may underlie such processes in acquired anti-hormone resistance and have identified several molecular elements through the study of cell models of acquired endocrine resistance.