Modulation of transforming growth factor beta expression and induction of apoptosis by tamoxifen in ER positive and ER negative breast cancer cells

Cross-talk between Transforming Growth Factor-β and Estrogen Receptor Signaling through Smad3

“…Reversal of the suppression of Smad3 activation by ER␣/E 2 by the anti-estrogen tamoxifen indicated that this effect is mediated directly by ER; both ER␣ and ER␤ had this activity. These findings are consistent with the reported therapeutic effects of anti-estrogens, such as tamoxifen, through local boosting of TGF-␤ signaling (43).…”

Tamoxifen Action in ER-Negative Breast Cancer

“…[37][38][39] In this context, the dose of tamoxifen used in the treatment may play an important role in determining whether tamoxifen will exert its usual ER-specific effect by acting as SERM when used in nanomolar dose range (100 nM to ,1000 nM) in ER-positive cells or its ER-independent effects both in ER-positive and in ER-negative breast cancer cells when used in dose range as high as $1 µmol. [40][41][42] Unlike its highly selective effect on ER in ER-positive breast cancer cells, tamoxifen has been found to exhibit off-target proapoptotic effects in ER-negative breast cancer cells. 37,[43][44][45][46] Some of the prominent ER-independent mechanisms reported by various studies are discussed in the following sections.…”

“…On the contrary, a study reported by Knabbe et al showed that TGFβ produced in the milieu of ER-positive MCF7 breast cancer cells can act in a negative paracrine manner to inhibit the growth of ER-negative breast cancer cells cocultured with ER-positive MCF7 breast cancer cells in response to tamoxifen treatment. 40,53,70 Moreover, TGFβ suppresses cell proliferation and promotes cellular differentiation and apoptosis in normal breast tissues and the early stages of breast cancer, whereas the same TGFβ promotes cell migration, invasion, and metastasis by inducing epithelial-to-mesenchymal transformation (EMT) in the later stages of breast cancer. 71 TGFβ-Akt signaling and their mediators regulating tamoxifen action.…”

Forkhead box protein A1 confers resistance to transforming growth factor‐β‐induced apoptosis in breast cancer cells through inhibition of Smad3 nuclear translocation

“…Tamoxifen is a selective ER modulator that is used for the treatment of estrogen-dependent breast cancer. The cytotoxic effect of tamoxifen depends on not only suppression of ER activity but also autocrine induction 23,24 of TGF-β1. Because FOXA1 is highly expressed in ER-positive breast cancer cells, FOXA1 is thought to suppress the cytotoxic effect of tamoxifen by inhibiting TGF-β1-induced apoptosis.…”

“…The ER antagonist tamoxifen promotes apoptosis of ERpositive breast cancer cells, and this cytotoxic effect depends on autocrine induction of TGF-β1. 23,24 We then examined the effect of FOXA1 knockdown on tamoxifeninduced apoptosis of ER-positive MCF7 cells. FOXA1 knockdown significantly enhanced cell death induced by tamoxifen treatment in MCF7 cells ( Figure 6A).…”