fig1

Figure 1. Mechanisms of endocrine resistance in breast cancer. Tamoxifen resistance has been associated with increased expression of the transcription factor SREBF (A). SREBF activates the transcription of mevalonate pathway (MVP) genes, like HMGCR (B). Activation of the mevalonate pathway induces prenylation of small GTPases such as Rho, Ras, or Rab (C). Ras prenylation leads to phosphorylation of PI3K (D), which activates Akt and mTOR to phosphorylate the residue, Ser167, of the estrogen receptor (ERa), which decreases sensitivity to tamoxifen (E). This leads to continued Era-derived transcription and phosphorylation of Rb, accelerating G1/S cell cycle transition (F). Ras phosphorylation also activates MEK (G), which activates ERK1/2. The latter is associated to a senescence-associated secretory phenotype (SASP) (H). Created with Biorender.com.