Actively growing
tumors are often histologically associated with Ki67 positivity, while the detection of invasiveness relies on non-quantitative pathologic evaluation of mostly advanced
tumors. We recently reported that reduced expression of the Ca2+-dependent membrane-binding
annexin A6 (AnxA6) is associated with increased expression of the Ca2+ activated RasGRF2 (
GRF2), and that the expression status of these
proteins inversely influence the growth and motility of
triple negative breast cancer (TNBC) cells. Here, we establish that the reciprocal expression of AnxA6 and
GRF2 is at least in part, dependent on inhibition of non-selective Ca2+ channels in AnxA6-low but not AnxA6-high TNBC cells. Immunohistochemical staining of
breast cancer tissues revealed that compared to non-TNBC
tumors, TNBC
tumors express lower levels of AnxA6 and higher Ki67 expression.
GRF2 expression levels strongly correlated with high Ki67 in pretreatment biopsies from patients with residual disease and with
residual tumor size following
chemotherapy. Elevated AnxA6 expression more reliably identified patients who responded to
chemotherapy, while low AnxA6 levels were significantly associated with shorter distant relapse-free survival. Finally, the reciprocal expression of AnxA6 and
GRF2 can delineate
GRF2-low/AnxA6-high invasive from
GRF2-high/AnxA6-low rapidly growing TNBCs. These data suggest that AnxA6 may be a reliable
biomarker for distant relapse-free survival and response of TNBC patients to
chemotherapy, and that the reciprocal expression of AnxA6 and
GRF2 can reliably delineate TNBCs into rapidly growing and invasive subsets which may be more relevant for subset-specific therapeutic interventions.