βIII-Tubulin Regulates Breast Cancer Metastases to the Brain

Abstract

Brain metastases occur in about 10–30% of breast cancer patients, which culminates in a poor prognosis. It is therefore critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (βIII tubulin, Nestin and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of βIII tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2 and MDA-MB-468) which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as β3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells.

2-(m-Azidobenzoyl)taxol binds differentially to distinct β-tubulin isotypes

“…Phosphatase and tensin homolog (PTEN)/AKT signaling has been demonstrated to be regulated by βIII-tubulin in NSCLC (42). In addition, a high percentage of breast cancer patients develop brain metastasis and βIII-tubulin overexpression is associated with brain metastasis (43). Recently, it was demonstrated that βIII-tubulin is involved in a complex, prosurvival molecular pathway induced by hypoxia (44).…”

High αv Integrin Level of Cancer Cells Is Associated with Development of Brain Metastasis in Athymic Rats

“…McCarroll et al (46) also showed that βIII-tubulin regulates lung cancer metastasis without altering growth of tumor cells in vivo in an anchorage-dependent manner. Parental (MDA-MB-231) and brain metastatic cells (MDA-MB-231BR) do not exhibit differences in proliferation, although MDA-MB- 231BR showed a 2.5-fold increase in βIII-tubulin protein levels (47). Jiang et al (48) also demonstrated that targeting αv integrin with abitumumab inhibited prostate cancer cell adhesion, migration and invasion, but not proliferation in vitro .…”

Exploring the key communicator role of exosomes in cancer microenvironment through proteomics

“…These include cytoskeleton proteins such as β-actin, tubulin-β, and integrins; membrane proteins like BASP1; enzymes including enolase α and PRDX1; ribosomal proteins like RS27A; heat shock proteins including HSP90A, HSP90B, HSP7C; and epigenetic modification related proteins such as Histone proteins and 14-3-3 proteins. β-actin and tubulin-β are associated with breast cancer metastasis [65,66]. Overexpression of these proteins in breast cancers show high metastatic potential.…”

“…In general, these cytoskeletal proteins of β-actin, tubulin-β and keratin are all associated with breast cancer metastasis. Fourteen other exosomal proteins are also known to be involved in the metastasis of breast cancer [65,66,86]. Tubulin-β is also known to induce chemotherapy resistance [87].…”

“…The main cause of the increasing incidence rate and mortality is not only primary tumors, but also distant tumors [122]. Many Tubulin-β Breast cancer metastasis, chemotheray resistance [66,87] Integrin α6/β4, α6/β1 Lung metastasis [32] Integrinαv/β5 Liver metastasis [32] BASP1 Overexpression leads to ovarian cancer cell progression [67] Enolase A Breast cancer metastasis and drug resistance [68,69] PRDX1 Induce cell growth in breast cancer and overexpressed in breast cancer [70] 14-3-3 protein Bind to histone protiens and induce epigenetic changes [75] Fibronectin Tumor progression and metastasis [76] Annexin A1 Induce tumor metastasis and macrophage polarization [78][79][80] 5'-NTD Overexpressed in breast cancer cells and induce metastasis [81][82][83][84][85] Survivin Overexpressed in breast cancer serum derived exoxome, Anti apoptosis [95] MTA1 Promote proliferation [96]…”