Abstract GS1-03: Crosstalk between osteoblasts and breast cancer cells alters breast cancer proliferation through multiple mechanisms

Abstract

BrCa preferentially metastasizes to bone, where the 5-year relative survival rate is In a cancer-free environment in the adult, the skeleton continuously undergoes remodeling. Osteoclasts excavate erosion cavities and osteoblasts (OB) synthesize bone matrix, with no net bone gain or loss. However, when metastatic BCC invade bone, this balance is disrupted to favor bone loss. Bisphosphonate treatments are not curative. OBs do not deposit new bone. This result suggests that OBs may be altered or experience a loss-of-function in the tumor niche. We have new, late-breaking evidence to suggest that communication between OBs and BCCs 9educates9 OBs to produce factors that suppress BCC proliferation in bone. We have in-vitro and in-vivo mouse-model evidence that 9educated9 osteoblasts (EOs) have a unique secretory protein profile compared to 9uneducated9 OBs. We also identified EOs as being present in the bone tissue samples of human patients with bone metastatic BrCa via multi-plex immunofluorescence. When we treated BCCs with EO conditioned media (CM), BCC proliferation was reduced in both triple negative and ER+ metastatic BCCs, while CM from 9uneducated9 OBs did not affect BCC proliferation. This effect was mediated through alterations in EO production of decorin and NOV. We identified EO CM as a rich source of exosomes (exo) and confirmed the presence of an exo population via iodixanol density gradient and western blotting for specific exo protein markers. We found that EO-derived exo, but not 9uneducated9 OB-derived exo, decreased proliferation of ER+ and triple negative BCC. Also, treatment with EO-derived exosomes increased the number of Ki67 negative metastatic BCC. Moreover, we labeled EO exo with RFP-conjugated CD63 to visually confirm exo transfer from EO cells to BCCs using confocal microscopy. And, co-culture with EOs increased triple negative and ER+ metastatic BrCa expression of p21 compared to co-cultures with 9uneducated9 OBs. Our data suggest that EOs use multiple mechanisms of cellular communication to regulate BCC proliferation in bone. Impact: Our late-breaking data suggest that OBs produce factors that suppress metastatic BCC growth. Much less attention has been given to OB interactions with tumor cells at sites of bone metastasis due to observations that OB populations are reduced at sites of advanced osteolysis. However, we propose that OBs may be valuable endogenous targets to aid in restoration of bone deposition and suppression of metastatic BrCa growth in the niche in concert with therapeutic drugs to kill the cancer cells. Our data suggest there is a population of OBs that demonstrate a functional role in retarding metastatic BCC growth; a property capable of exploitation. Moreover, restoration of the OBs9 ability to deposit new bone would lead to better quality of life and increased time of survival for bone metastatic BrCa patients where bone loss is found. For these reasons, OBs and EOs are suitable candidates for therapeutic targeting and will open new avenues for retarding the growth of BrCa bone metastases. Citation Format: Bussard KM, Shupp AB, Kolb AD, Mukhopdhyay D. Crosstalk between osteoblasts and breast cancer cells alters breast cancer proliferation through multiple mechanisms [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 GS1-03.