Stage of Breast Cancer Progression Influences Cellular Response to Activation of the WNT/Planar Cell Polarity Pathway

Abstract

Planar cell polarity (PCP) signaling has been shown in different studies to either promote or inhibit the malignancy of breast cancer. Using the 21T cell lines, which were derived from an individual patient and represent distinct stages of progression, we show that the prototypical PCP ligand, WNT5A, is expressed highest in 21MT-1 cells (invasive mammary carcinoma) and lowest in 21PT (atypical ductal hyperplasia) and 21NT (ductal carcinoma in situ) cells. Overexpression of WNT5A decreased spherical colony formation and increased invasion and in vivo extravasation only in 21NT cells; whereas overexpression increased migration of both 21PT and 21NT cells. WNT5A overexpression also increased RHOA expression of both cell lines and subsequent RHOA knockdown blocked WNT5A-induced migration, but only partially blocked WNT5A-induced invasion of 21NT cells. PCP can signal through VANGL1 to modulate AP-1 target genes (e.g. MMP3) and induce invasion. VANGL1 knockdown inhibited WNT5A-induced invasion of 21NT cells, but had no effect on WNT5A-induced migration of either 21PT or 21NT cells. WNT5A-induced MMP3 expression was seen only in 21NT cells, an effect that was VANGL1 dependent, but independent of AP-1. We thus provide evidence that PCP signaling can act in a context dependent manner to promote breast cancer progression.

VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix

“…Published data suggest that VANGL2 might also suppress the growth of certain types of tumors [70, 71]. Interestingly, increased expression of the VANGL2 homologue VANGL1 has been linked to tumor progression and increased malignancy [72, 73]. While both VANGL2 and VANGL1 regulate neural tube closure [74], only VANGL2 is required for PCP during zebrafish gastrulation [75].…”

Planar cell polarity in moving cells: think globally, act locally

“…The downregulation of FZD6, DVL1, VANGL1, PK1 and WNT11 reduces protrusive activity and migration of breast cancer cells (BCCs), and PK1 is required to promote BCC metastasis in mice (Luga et al, 2012). Additionally, a link between FZD2, DVL1, VANGL1, SCRIB and WNT5A and cancer cell motility has been shown in several cancer cell lines (Anastas et al, 2012;Gujral et al, 2014;MacMillan et al, 2014;Yamamoto et al, 2010). A model for how PCP signaling regulates the migration of individual cancer cells has recently been proposed.…”

Multiple Roles of WNT5A in Breast Cancer

“…MacMillan et al found that WNT5A is expressed at highest levels in 21MT-1 cells (invasive mammary carcinoma) and at lowest levels in 21PT (atypical ductal hyperplasia) and 21NT (ductal carcinoma in situ ) cells [20]. …”