Newly-designed selective estrogen receptor downregulators and their role in the tumor microenvironment and hematopoiesis in breast malignancies

Breast cancers (BC) with estrogen receptor-alpha (ERalpha) expression represent 70% of newly-diagnosed patients in the US. Endocrine therapies with antiestrogens or aromatase inhibitors, either alone or combined with CDK 4/6 inhibitors, are an important intervention for BCs that express ERalpha, and these remain among the most effective targeted treatment strategies. However, a number of patients with localized BC, and essentially all patients with advanced BC, eventually become resistant to current endocrine therapy regimens. In contrast, immunotherapy is transforming the landscape of treatment for many cancers. However, most breast cancers, apart from a minority of triple-negative breast cancers (TNBC), are resistant to this promising immunotherapeutic approach. Several mechanisms of immune resistance have been described. Of note, BCs are reported to drive expansion and differentiation of hematopoietic stem and progenitor cells in the bone marrow to skew hematopoiesis toward an immunosuppressive myeloid lineage. This dysregulation of myelopoiesis in breast malignancy leads to aberrant expansion of immunosuppressive and tumor-promoting myeloid subpopulations such as myeloid-derived suppressor cells (MDSCs). Our newly-designed selective estrogen receptor down-regulator JD128 (SERDs) markedly reduces in vitro proliferation of several ERalpha+ BC cell lines, alone and combined with CDK 4/6 inhibitors, when compared with FDA-approved SERDs Fulvestrant and Elacestrant (P< 0.01). This was accompanied by a significant decrease of ERalpha protein as well as mRNA levels, confirming ERalpha protein degradation. Further, estrogen stimulated proliferation of CD34+ bone marrow stem cells, multipotent progenitors and MDSCs derived from normal female donors, an effect that was inhibited by SERD JD128 and Fulvestrant indicating that hematopoietic stem and progenitor cells express estrogen receptors and respond to estrogen. In addition, SERD JD128 inhibited proliferation of BC cell mammospheres and reduced expression of cancer stem cell markers. Importantly, accumulation and activity of MDSCs that occupy the tumor microenvironment (TME) appear to occur in both ER-positive and ER-negative tumors. Moreover, estrogen-responsive MDSCs in the TME can be targeted by SERD therapy to block estrogen signaling. These estrogen-mediated effects on hematopoietic cell expansion/activation have implications for potential clinical use of SERDs in ER-positive or ER-negative BCs. [Funded by: CIRM DISC2-14166, UCLA JCCC Breast Cancer Award, Tower Cancer Research Foundation, Hickey Foundation, NIH/NCI U54 CA143930 CDU-UCLA JCCC Partnership, CBCRP B27IB3869, DOD BCRP Level 2-BC181420]