We have previously reported that induction of epidermal growth factor receptor (EGFR) and ErbB2 in response to antihormonal agents may provide an early mechanism to allow breast cancer cells to evade the growth inhibitory action of such therapies and ultimately drive resistant cell growth. More recently, the other two members of the ErbB receptor family, ErbB3 and ErbB4, have been implicated in antihormone resistance in breast cancer. In the present study we have investigated whether induction of ErbB3 and/or ErbB4, may provide an alternative resistance mechanism to antihormonal action in a panel of four oestrogen receptor (ER)-positive breast cancer cell lines.

MCF-7, T47D, BT474 and MDAMB361 cell lines were exposed to fulvestrant (100 nM) for 7 days and effects on ErbB3/4 expression and signalling and cell growth were assessed. Effects of heregulin-beta1 (HRGbeta1) were also examined in the absence and presence of fulvestrant. to determine the impact of ER blockade on the capacity of this ErbB3/4 ligand to promote signalling and cell proliferation.

Fulvestrant potently reduced ER expression and transcriptional activity and significantly inhibited growth in MCF-7, T47D, BT474 and MDAMB361 cells. However, alongside this inhibitory activity, fulvestrant also consistently induced protein expression and activity of ErbB3 in MCF-7 and T47D cells and ErbB4 in BT474 and MDAMB361 cell lines. Consequently, fulvestrant treatment sensitised all cell lines to the actions of the ErbB3/4 ligand heregulin beta1 with enhanced ErbB3/4-driven signalling activity, re-expression of cyclin D1 and significant increases in cell proliferation being observed when compared to untreated cells. Indeed, in T47D and MDAMB361 heregulin beta1 was converted from a ligand having negligible or suppressive growth activity into one that potently promoted cell proliferation. Consequently, fulvestrant-mediated growth inhibition was completely overridden by heregulin beta1 in all four cell lines.

These findings would suggest that although antihormones, such as fulvestrant, may have potent acute growth inhibitory activity in ER-positive breast cancer cells their ability to induce and sensitize cells to growth factors may serve to reduce and ultimately limit their inhibitory activity.

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