Developing strategies to block the survival of dormant breast cancer stem cells in order to improve patient outcomes.
 

Impact

Development of resistance to endocrine therapy (tamoxifen and/or aromatase inhibitors) for estrogen receptor (ER)-positive breast cancer or to chemotherapy for triple-negative breast cancer (TNBC) remains a clinical challenge. Breast cancer stem cells (BCSCs) , are the tumor cells most likely to survive anti-cancer therapies and cause breast cancer recurrence many years later. Drs. Osipo and Albain are focused on defining the mechanisms involved in BCSC survival that may be targeted to prevent treatment resistance. With BCRF support, they have identified key pathways involved in the resistance of BCSCs to cancer treatment and demonstrated that a gene called DAXX is a potent inhibitor of BCSCs. They have shown that high amounts of the DAXX gene correlates with a reduction in the number of BCSCs and a better response to endocrine therapy, standard chemotherapy, and PARP inhibitor treatment in ER-positive and TNBC cells. Further work has the potential inform the development of new strategies to reduce drug resistance in ER-positive and TNBC. 

Progress Thus Far

Drs. Osipo and Albain have shown that increasing DAXX levels in breast cancer cells effectively kills all breast cancer cells including BCSCs. In addition, they found high levels of the DAXX gene in ER-positive breast cancer cells inhibited endocrine therapy resistance  and DAXX status also predicted sensitivity to chemotherapy, DNA damage response, and PARP inhibition in TNBC cells. For other studies, they collected breast cancer biopsies before and after pre-surgical (neoadjuvant) endocrine therapy or chemotherapy  to determine how the levels of DAXX and other cancer stem cell biomarkers are affected by neoadjuvant therapies. In the last year, the team has fully characterized these samples, assembled a large comprehensive database, and initiated analysis of DAXX and biomarkers.  

What’s next

Drs. Osipo and Albain will use the  a large national tumor biorepository to correlate biomarker status with response to neoadjuvant therapy and validate their results regarding the potential for DAXX and other biomarkers to predict response to endocrine therapy for ER-positive breast cancer and/or chemotherapy for TNBC.  They will also continue to investigate the mechanism by which DAXX turns off BCSC genes to identify strategies to target BCSC and decrease breast cancer resistance to treatment.