βIII-Tubulin Regulates Breast Cancer Metastases to the Brain.
Brain metastases occur in about 10% to 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.
The Brain Tumor Center, The University of Chicago, Chicago, Illinois.
Deepak
D
Kanojia
The Brain Tumor Center, The University of Chicago, Chicago, Illinois.
Ramin A
RA
Morshed
The Brain Tumor Center, The University of Chicago, Chicago, Illinois.
Lingjiao
L
Zhang
The Brain Tumor Center, The University of Chicago, Chicago, Illinois.
Jason M
JM
Miska
The Brain Tumor Center, The University of Chicago, Chicago, Illinois.
Jian
J
Qiao
The Brain Tumor Center, The University of Chicago, Chicago, Illinois.
Julius W
JW
Kim
Department of Pathology, University of Chicago Medical Center, Chicago, Illinois.
Peter
P
Pytel
The Brain Tumor Center, The University of Chicago, Chicago, Illinois.
Irina V
IV
Balyasnikova
The Brain Tumor Center, The University of Chicago, Chicago, Illinois. mlesniak@surgery.bsd.uchicago.edu.
Maciej S
MS
Lesniak
The Brain Tumor Center, The University of Chicago, Chicago, Illinois.
Atique U
AU
Ahmed
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D014404:Tubulin / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
C498585:TUBB3 protein, human; D014404:Tubulin