Although, HER2+ tumors are commonly considered as a single entity, there is increasing evidence indicating that important intrinsic differences associated to hormone receptor status (HR) exist. Each of the two groups, HR+ and HR-, represent about ½ of all HER2+ breast cancers.

Compared to HR+/HER2+, HR-/HER2+ tumors present worst histopathological characteristics. HR+/HER2+ tumors preferentially recur in bone while there is a strong trend for more visceral metastases in the HR-/HER2+ cancers. Moreover, despite a higher rate of pathologic complete responses (pCR) to neoadjuvant chemotherapy HR-/HER2+ patients still have an increased risk of death within five years of diagnosis. Intrinsic differences between HR-/HER2+ and HR+/HER2+ breast cancers are also found at the molecular level, as highlighted by unsupervised cluster analysis of gene expression profiles. The latter clear identifies two distinct HER2+ subtypes. Most tumors clinically classified as HR+/HER2+ fall in the luminal B subtype, while most HR-/HER2+ are part of the HER2 enriched subtype.

Indeed, while HR+/HER2+ patients benefit from anti-hormonal and HER2 targeted therapies, the outcome of HR-/HER2+ patients strongly depends on their response to chemotherapy as well as anti-HER2 therapy. Thus, to identify genes that represent novel mechanistic dependencies in HR-/HER2+ breast cancer cells, we designed an integrative approach that combines functional genomic (RNAi screens) and computational algorithms.

Our integrative analysis (IN PRESS GENES & DEVELOPMENT) identified STAT3 as a de novo master regulator (MR) gene associated to HER2 mediated transformation in HR- breast cancer cells. Importantly, we demonstrate that aberrant STAT3 activity is necessary to maintain HR-/HER2+ tumor state, thus representing a non-oncogene dependency in these tumors. Mechanistically we found that HR-/HER2+ breast tumors secrete high levels of IL-6. This autocrine mechanism induces the activation of STAT3 via the canonical JAK2/STAT3 pathway. Aberrant STAT3 activity induces upregulation and secretion of the S100A8/9 complex (Calprotectin), thus triggering a second autocrine stimulus that enhances proliferation and survival. As a result, disruption of the “IL-6-JAK2-STAT3-S100A8/9 cascade” compromises HR-/HER2+ cell viability suggesting that the components of this pathway represent putative therapeutic targets in HR-/HER2 tumors. Importantly, small molecule inhibitors and blocking antibodies for components of this double autocrine loop are already FDA approved or in clinical trials. Here, we demonstrate that blocking the IL-6 receptor (IL-6R) with the humanized monoclonal antibody Tocilizumab, STAT3 inactivation with the dual JAK1/2 inhibitor Ruxolitinib or Calprotectin inhibition with the small molecule inhibitor Tasquinimod, alone or in combination with anti HER2 therapies, compromises the viability of HR-/HER2+ breast cancer cells. Availability of FDA-approved inhibitors to target this novel mechanism represents an exciting opportunity for rapid translation of these findings to the clinics.

Note: This abstract was not presented at the conference.

Citation Format: Ruth Rodriguez-Barrueco, Jiyang Yu, Andrea Califano, jose silva. Inhibition of the autocrine IL-6-JAK2-STAT3-Calprotectin axis as targeted therapy for HR-/HER2+ breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B36.

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.