Abstract 2158: Inhibition of NFkB restores tamoxifen responsiveness in resistant estrogen receptor positive breast cancer in a syngeneic mouse model

Breast cancer is responsible for 23% of new cancer cases per year worldwide and is the most frequently diagnosed cancer in women. Approximately 75% of breast cancers express the estrogen receptor (ER), and are subsequently treated with endocrine therapies. Despite initial therapeutic response, around 50% of ER positive tumors will recur and are often more aggressive and resistant to therapy. Consequently, overcoming resistance is paramount in moving towards more effective treatments for breast cancer. Studies are hindered by the lack of models that effectively recapitulate a physiologically relevant in-vivo environment with an intact microenvironment and functional immune system, both of which are important in affecting tumor response. The use of syngeneic mouse models overcomes this and allows us to more accurately replicate therapy response in-vivo. There are multiple mouse cell lines that are described as ER positive, however many do not respond to tamoxifen. These may represent a suitable archetype to study endocrine resistance and the underlying mechanism associated with this phenotype, both in-vitro and in a syngeneic in-vivo mouse model. J110 and Py2T cells are both described as ER positive and recognized as being tamoxifen resistant by our group and others. We have confirmed mRNA and protein expression of ER in these cells, however expression of ER target genes is unaffected by estradiol (E2) or tamoxifen treatment. Using a proliferation assay we demonstrated that cells are unresponsive to E2, tamoxifen and fulvestrant (ICI), suggesting resistance to ER ligands. A screen of pathways inhibitors found that IKK inhibitor VII and dimethyl fumarate, both directed at the NF-kB pathway, were able to sensitize cells to the anti-proliferative effects of tamoxifen. This effect translates in-vivo, where mice treated with tamoxifen and DMF, showed significantly reduced tumor growth compared to control groups. In agreement with our data, in-vitro studies have shown that repression of NF-kB can restore sensitivity to endocrine agents. There is considerable evidence that resistance and therapeutic failure in ER positive tumors may be partly attributed to the activation of NF-kB signaling, therefore NF-kB presents as an attractive target to overcome resistance. We have confirmed that NF-kB is active in mouse cell lines in-vitro, and that both cell lines are migratory and invasive in-vitro, suggesting a more aggressive phenotype than is typically observed in ER pos