Journal Article

Reciprocal expression of Annexin A6 and RasGRF2 discriminates rapidly growing from invasive triple negative breast cancer subsets

Washington, Mary Kay, Reisenbichler, Emily, Whalen, Diva S., Widatalla, Sarrah E., Ochieng, Josiah, Nangami, Gladys N., Sakwe, Amos M., Beasley, Heather K., Lehmann, Brian D., Mayer, Ingrid A., Abimbola, Adeniyi, Williams, Stephen D., Korolkova, Olga Y.

2020

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Annexin A6 - genetics / Annexin A6 - metabolism / Bepridil / Biochemistry / Biology / Biology and Life Sciences / Biomarkers / Biomarkers, Tumor - genetics / Biomarkers, Tumor - metabolism / Biopsy / Breast cancer / Calcium Channel Blockers - pharmacology / Calcium channels / Calcium Channels - metabolism / Calcium ions / Cancer / Cancer therapies / Carboplatin / Cell growth / Cell Line, Tumor / Cell Movement - genetics / Cell Proliferation - genetics / Chemotherapy / Cytotoxicity / Development and progression / Female / Gene expression / Graduate studies / Health aspects / Homeostasis / Humans / Immunohistochemistry / Invasiveness / Ki-67 Antigen - metabolism / Medical schools / Medicine and Health Sciences / Metastasis / Mice / Motility / Neoplasm Metastasis - genetics / Neurosciences / Pathology / Patients / Pharmacology / Prognosis / Proteins / ras Guanine Nucleotide Exchange Factors - genetics / ras Guanine Nucleotide Exchange Factors - metabolism / Survival / Therapeutic applications / Transplantation, Heterologous / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - mortality / Triple Negative Breast Neoplasms - pathology / Tumors