Identifying a Novel Diagnostic and Therapeutic Target for Metastatic Breast Cancer

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Michele Vitolo photoDr. Michele I. Vitolo

University of Maryland, Baltimore, MD

With metastasis posing the primary challenge in the clinical management of breast cancer, there is high demand for effective diagnostic and therapeutic strategies focused on this facet of the disease. In this webinar, Dr. Michele Vitolo from the University of Maryland discusses the multi-pronged approach her lab has used to identify a tight correlation between acetylated alpha-tubulin levels and aggressive metastatic behavior in breast cancer. The implications for defining a simple prognostic biomarker in patients with breast cancer is presented. Other topics covered include:

  • An overview of microtentacles and their function in promoting metastatic reattachment of circulating tumor cells in distant tissues.
  • Using impedance-based label-free real-time xCELLigence® technology to quantitatively access the role of alpha-tubulin acetylation on breast cancer cell adhesion, invasion and migration properties
  • The correlation between increased alpha-tubulin acetylation and lymph node metastases, increased risk of disease progression, and death in patients

Dr. Michele I. Vitolo obtained her B.S. at Franklin and Marshall College and her Ph.D. at the University of Maryland, Baltimore where she is currently an assistant professor of physiology in the School of Medicine. Dr. Vitolo has a long-standing interest in the molecular genetics of cancer. Her work has focused on PTEN loss and the progression of breast cancer. PTEN loss and the acquisition of PIK3CA activating mutations are often assumed to be reciprocal and mutually exclusive mutations, each resulting in the unregulated activation of the PI3K/Akt signaling pathway. However, she and her colleagues have recently reported differences in cytoskeletal structure and signaling between PTEN loss and PI3K activation. This finding could have new implications for patients with PTEN loss that are on current PI3K inhibitor therapies, possibly resulting in reduced drug efficacy. Currently, her research interests are focused on: 1) how the loss of PTEN promotes apoptosis-resistant cells which continue to respond cytoskeletally to the challenging environment of the bloodstream during metastasis, and 2) elucidating the cytoskeletal structural and signaling differences in cells with PTEN loss and PI3K activation.

REFERENCES:

  1. Matrone, M.A., Whipple, R.A., Thompson, K., Cho, E.H., Vitolo, M.I., Balzer, E.M., Yoon, J.R., Ioffe, O.B., Tuttle, K.C., Tan, M. and Martin, S.S. Metastatic breast tumors express increased tau, which promotes microtentacle formation and the reattachment of detached breast tumor cells. Oncogene. 2010 Jun 3;29(22):3217-27.
  2. Whipple, R.A., Cho, E.H., Balzer, E.M., Matrone, M.A., Vitolo, M.I., Yoon, J.R., Ioffe, O.B., Tuttle, K.C., Yang, J. and Martin, S.S. Epithelial-to-mesenchymal transition promotes tubulin detyrosination and microtentacles that enhance endothelial engagement. Cancer Res. 2010 Oct 15;70(20):8127-37.
  3. Yoon, J.R., Whipple, R.A., Balzer, E.M., Cho, E.H., Matrone, M.A. and Martin, S.S. Local anesthetics inhibit kinesin motility and microtentacle protrusions of human epithelial and breast tumor cells. Breast Cancer Res. Treat. 2011 Oct;129(3):691-701.
  4. Vitolo MI, Boggs AE, Whipple RA, Yoon JR, Thompson K, Matrone MA, Cho EH, Balzer EM, Martin SS. Loss of PTEN induces microtentacles through PI3K-independent activation of cofilin.Oncogene. 2013 Apr 25;32(17):2200-10.
  5. Whipple RA, Vitolo MI, Boggs AE, Charpentier MS, Thompson K, Martin SS.Parthenolide and costunolide reduce microtentacles and tumor cell attachment by selectively targeting detyrosinated tubulin independent from NF-κB inhibitionBreast Cancer Res. 2013; 15(5):R83.
  6. Charpentier MS, Whipple RA, Vitolo MI, Boggs AE, Slovic J, Thompson KN, Bhandary L, Martin SS. Curcumin targets breast cancer stem-like cells with microtentacles that persist in mammospheres and promote reattachment. Cancer Res. 2014 Feb 15;74(4):1250-60.
  7. Perry NA, Vitolo MI, Martin SS, Kontrogianni-Konstantopoulos A. Loss of the obscurin-RhoGEF downregulates RhoA signaling and increases microtentacle formation and attachment of breast epithelial cells. Oncotarget. 2014 Sep 30;5(18):8558-68.
  8. Boggs AE, Vitolo MI, Whipple RA, Charpentier MS, Goloubeva OG, Ioffe OB, Tuttle KC, Slovic J, Lu Y, Mills GB, Martin SS. α-Tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion, and invasive migration. Cancer Res. 2015 Jan 1;75(1):203-15.
  9. Bhandary L, Whipple RA, Vitolo MI, Charpentier MS, Boggs AE, Chakrabarti KR, Thompson KN, Martin SS. ROCK inhibition promotes microtentacles that enhance reattachment of breast cancer cellsOncotarget. 2015 Mar 20;6(8):6251-66.