Discussion This is the first report of an ER-negative phenotype changing to ER positive after a trastuzumab-containing therapy in patients with advanced breast cancer. Interestingly, previous reports evaluating the use of trastuzumab in the preoperative setting in patients with locally advanced breast cancer do not address this particular issue.[12,13] The patient sample was limited, but this could be an important anecdoctal and hypothesis-generating report that should be confirmed in larger trials. Another potential limit was that the reassessment was performed at a variable time point after the start of therapy, and the timing was not predefined. Our three patients had a reversion of ER to a positive phenotype after 9, 12 and 37 weeks from the start of treatment with trastuzumab. For this reason we do not have data on which to base a hypothesis about the optimal timing for performing the reassessment. A recent report by Arpino et al. proposed that a lack of PgR expression could be a reflection of active signaling in the HER family and, as a consequence, the response to trastuzumab might be different in the PgR-positive and PgR-negative subsets.[14] Interestingly, two of our patients after ER reversion to a positive phenotype remained PgR negative; both had a partial response to trastuzumab, whereas the only patient who also had a PgR reversion was resistant to trastuzumab. Other studies that address ER loss reversibility in breast cancer cell lines involve treatments with demethylating agents such as 5-azacytidine.[15,16] About 25% of ER-negative breast tumors were found to contain methylated ER.[17] However, several ER-positive tumors also showed similar degrees of methylation.[18] Methylation, by modifying the DNA structure assisting in the recruitment of histone deacetylases, ensures that the gene is in an inactive conformation. If methylation occurs as a step subsequent to another mechanism of ER repression, one would predict that some ER-negative breast tumors at an earlier point in a progression pathway do not express ER because one of these other mechanisms is still operative. In such tumors, it might then be possible to reverse this phenotype and restore antiestrogen sensitivity, perhaps by using a demethylating agent. An interesting recently reported transcription factor that might be linked to hormone-independent breast cancer, as well as elevated growth factor signaling, is NF-ęB. Its activity is elevated in hormone-independent breast cancer, and it is implicated in enhanced cell survival and chemoresistance in cancer.[19] Holloway et al. have shown recently that an elevation in NF-ęB activity is attributable to enhanced growth factor signaling through ERK1/2; inhibiting this NF-ęB activity, either pharmacologically or through the expression of a constitutively active IęB, partly restores ER activity and expression in these cells. These findings suggest a role for cytoplasmic substrates of MAPK in ER downregulation in breast cancer and further support a role for MAPK-induced NF-ęB activity in this downregulation.[20] Conclusion We conclude that our clinical data – although limited in the patient sample – support previous assessments in vitro, suggesting that an ER-negative phenotype may be a multi-step process with a reversible repression modality, and that some ER-negative tumors might revert to the ER-positive phenotype allowing an endocrine-based treatment. Although further studies are essential to show that inhibitors of mitogenic signaling can restore ER expression and/or function in breast tumors, coupling molecules such as signal transduction inhibitors, monoclonal antibodies, demethylating agents or NF-ęB inhibitors with antiestrogens could result in therapies that are better tolerated and active for the treatment of ER-negative breast cancer. In addition, once the MAPK substrate or substrates responsible for ER downregulation are identified, they could provide an additional drug target. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.