Abstract P2-06-23: New biomarkers for adjuvant bisphosphonate use in triple-negative breast cancer

Abstract

We first showed that triple-negative breast cancer (TNBC) patients with low Toll-like receptor 9 (TLR9) expression have significantly worse prognosis than patients with high TLR9 expression. TLR9 is an innate immunity DNA receptor which is also expressed in several cancers, including TNBC. Later, we showed that low-TLR9 cells and tumors are more sensitive to amino-bisphosphonates, especially to zoledronate. Bisphosphonates (BP) inhibit osteoclasts and thereby effectively prevent bone fractures in osteoporosis and in cancer-induced bone disease. BPs also have direct anticancer effects. Interestingly, adjuvant BP use is associated with significantly improved progression-free and overall survival, but only among post-menopausal breast cancer patients. The molecular mechanisms behind this observation is unclear. CD73 is a 70 kDa glycophosphatidylinositol-anchored cell protein, which converts adenosine monophosphate to adenosine and organic phosphate. High CD73 expression has been shown to have cancer cell invasion-promoting properties. On the other hand, CD73 is associated with poor prognosis in TNBC. Interestingly, TLR9 and CD73 have been shown to have inverse relationship in T cells and during colonic inflammation. Currently, we study the relationship of CD73 and TLR9 in vitroand in vivo upon BP treatment. Our preliminary results show that TLR9 and CD73 have an inverse relationship also in TNBC cells. We use both nitrogen-containing (zoledronate and alendronate) and pyrophosphate-like (clodronate) BPs together with doxorubicin to study TNBC cell responses. We have seen that zoledronate and alendronate, but not clodronate, inhibited 4T1 murine triple-negative mammary tumor cell proliferation in a dose-dependent manner. Also, high concentrations of zoledronate and alendronate significantly inhibited 4T1 cell migration. Additionally, CD73 shRNA cells are more sensitive to zoledronate and alendronate, showing morphological changes and disruption in actin organization. Our results suggest that CD73 expression may affect treatment responses to BPs in TNBC. Further, low-CD73 tumors could benefit more of BP therapy, compared with high-CD73 tumors. Citation Format: Sandholm JA, Petruk N, Selander KS, Tuomela JM. New biomarkers for adjuvant bisphosphonate use in triple-negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-23.

A Review of Literature on Updates of Bisphosphonates Administration, Cancer Biomarkers for Bisphosphonate Therapy, and Bisphosphonate-related Osteonecrosis of the Jaw in Breast Cancer

“…The fact that non-nitrogencontaining BPs are considered anti-inflammatory while nitrogen-containing BPs are pro-inflammatory agents, explains why the findings were most pronounced with n-BPs. Again, Sandholm et al (23) have recognized a cell protein entitled CD73 as another important biomarker in breast cancer associated with BP adjuvant therapy. Similar to TLR9, low-CD73 breast cancer tumors tend to benefit from adjuvant therapy with BPs.…”