Bone is a major site for the preferential metastasis by advanced breast cancers. Bone metastases by breast cancers cause deadly complications and there is an unmet need for efficacious intervention with minimal side effect. The majority of previous studies have primarily focused on metastasized cancer cells or tumor supporting bone microenvironments. Here we propose to investigate the intrinsic anti-cancer metastatic potentials of the osteocytes, the most abundant bone cell type in the bone. Connexin (Cx) 43 hemichannels are richly present in osteocytes. Our preliminary study showed that the opening of Cx43 hemichannels by either bisphosphonate drugs or mechanical stimulation inhibited migration and anchorage-independent growth of breast cancer cells. Moreover, breast cancer bone metastasis appears to be augmented in osteocyte-specific Cx43 knockout mice when compared to wild-type controls. As such, we hypothesize that active Cx43 hemichannels in osteocytes release ATP and ATP acting in a paracrine manner activates purinergic receptor signaling in breast cancer cells, leading to the suppression of breast cancer bone metastasis. The goal is to establish the importance of osteocytic Cx43 hemichannels as a potential, novel drug target for the treatment. In this proposal, first, we will test the hypothesis that active osteocytic Cx43 hemichannels inhibit breast cancer cell metastasis. The effect of Cx43 hemichannel inhibition on breast cancer bone metastasis will be examined in vivo using in-house developed Cx43-deficient mouse models and hemichannel-specific blocking antibodies. The cell-based studies will be used to dissect the effect of osteocytic Cx43 hemichannels on various subtypes of breast cancer cells. Second, we will test the hypothesis that osteocytic Cx43 hemichannels activated by mechanical loading, associated with physical exercise, plays a critical role in the inhibition of breast cancer bone metastasis. We will apply mechanical loading through flow shear stress in vitro and tibial loading in vivo to assess the functional involvement of osteocytic Cx43-hemichannels in breast cancer migration and bone metastasis, and on bone cell function and bone strength, as the latter could serve as a complementary defense mechanism against bone metastasis. Third, we will test the hypothesis that P2X7 receptor in breast cancer cells activated by ATP released by osteocytic Cx43 hemichannels is responsible for the suppression of bone metastasis by first investigating the roles of ATP and P2X7 purinergic receptor, and followed by studying the underlying mechanism concerning how the activation of P2X7 receptor-mediated signaling inhibits breast cancer cell function and if down-regulation of this mechanism is more prevalent in clinical samples associated with bone metastases. Through a unique collaboration with the laboratories of the two PIs with their strong, complementary expertise, the proposed studies are expected to reveal a novel, inhibitory mechanism in the suppression of breast cancer bone metastasis, and should make significant contributions to the discovery of new therapeutic targets for the treatment of breast cancer-induced bone metastases.

Public Health Relevance

Breast cancer metastasizing to the bone is a deadly complication, occurring in up to 80% of patients with advanced breast cancers. The proposed research will investigate an intrinsic, self-protective mechanism of bone cells via connexin hemichannels, ATP and purinergic receptors in suppression of breast cancer growth and metastasis. The outcomes of the proposed research activities are expected to make novel, significant contributions to the discovery of drug targets and biomarkers for the treatment of breast cancer bone metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Progression and Metastasis Study Section (TPM)
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Woodhouse, Elizabeth
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University of Texas Health Science Center
Schools of Medicine
San Antonio
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Iyyathurai, Jegan; Wang, Nan; D'hondt, Catheleyne et al. (2018) The SH3-binding domain of Cx43 participates in loop/tail interactions critical for Cx43-hemichannel activity. Cell Mol Life Sci 75:2059-2073
Zhu, Haiyan; Xia, Lu; Shen, Qi et al. (2018) Differential effects of GLI2 and GLI3 in regulating cervical cancer malignancy in vitro and in vivo. Lab Invest 98:1384-1396
Xu, Huiyun; Duan, Jing; Ren, Li et al. (2018) Impact of flow shear stress on morphology of osteoblast-like IDG-SW3 cells. J Bone Miner Metab 36:529-536
Graham, Sheila V; Jiang, Jean X; Mesnil, Marc (2018) Connexins and Pannexins: Important Players in Tumorigenesis, Metastasis and Potential Therapeutics. Int J Mol Sci 19:
Tarzemany, Rana; Jiang, Guoqiao; Jiang, Jean X et al. (2018) Connexin 43 regulates the expression of wound healing-related genes in human gingival and skin fibroblasts. Exp Cell Res 367:150-161
Xu, Huiyun; Ning, Dandan; Zhao, Dezhi et al. (2017) Blockage of hemichannels alters gene expression in osteocytes in a high magneto-gravitational environment. Front Biosci (Landmark Ed) 22:783-794
Tarzemany, Rana; Jiang, Guoqiao; Jiang, Jean X et al. (2017) Connexin 43 Hemichannels Regulate the Expression of Wound Healing-Associated Genes in Human Gingival Fibroblasts. Sci Rep 7:14157
Xu, Huiyun; Liu, Ruofei; Ning, Dandan et al. (2017) Biological responses of osteocytic connexin 43 hemichannels to simulated microgravity. J Orthop Res 35:1195-1202
Zhou, J Z; Riquelme, M A; Gu, S et al. (2016) Osteocytic connexin hemichannels suppress breast cancer growth and bone metastasis. Oncogene 35:5597-5607
Shi, Qian; Jiang, Jean X (2016) Connexin arrests the cell cycle through cytosolic retention of an E3 ligase. Mol Cell Oncol 3:e1132119

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