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The role of podocalyxin in breast cancer progression and metastasis

University of British Columbia

The molecular heterogeneity of breast cancers makes them very challenging to diagnose and treat. While many breast tumors are curable surgically, others have an increased tendency to relapse or metastasize. Podocalyxin (gene name PODXL) is a CD34-related sialomucin that is important in regulating cell adhesion, migration, and polarity of hematopoietic progenitors and vascular endothelia. Previously, podocalyxin expression in primary breast tumor cells has been correlatively linked to poor patient survival. In addition, overexpression of podocalyxin in MCF-7 luminal breast cancer cells results in an overall increase in aggressive morphological features including: apical bulging, microvillus formation, and disrupted integrin targeting to the basolateral surface. To determine whether podocalyxin has a definitive role in breast tumor progression, I used shRNA-based vectors to silence expression of PODXL in a basal-like breast cancer cell-line, MDA.MB-231, which normally expresses high levels of endogenous podocalyxin, forms poorly polarized monolayers and tumorspheres in vitro and rapidly forms metastatic tumors in vivo. I found that podocalyxin impairs adhesion to extracellular matrices (ECM) and is critical for the formation of tumorspheres in vitro. In addition, I found that podocalyxin expression is critical for both primary tumor development and the formation of distant metastases in the lung, liver, and bone marrow in xenografted mice. These findings were corroborated by use of a mouse mammary tumor cell line (4T1) in a syngeneic model of metastatic tumor progression. Furthermore, in collaboration with the Centre for Drug Research and Development (UBC), I evaluated the ability of candidate therapeutic antibodies to podocalyxin to block the growth and metastasis of established tumors. One candidate antibody, known as anti-PODO, was found to significantly inhibit primary tumorigenesis in a pre-clinical mouse model. In summary, in this thesis I demonstrate for the first time that podocalyxin plays a causal role in promoting the growth of solid tumors and enhancing metastasis of tumor cells to distant organs. These findings have the potential to improve treatments for breast cancer patients by providing a highly specific and well-tolerated adjuvant therapy for metastatic disease.

Text

2015-02-28

CC0 1.0 Universal

http://hdl.handle.net/2429/46014

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/publicdomain/zero/1.0/