Reduced CREB3L1 expression in triple negative and luminal a breast cancer cells contributes to enhanced cell migration, anchorage-independent growth and metastasis

Abstract

Women with metastatic breast cancer have a disheartening 5-year survival rate of only 28%. CREB3L1 (cAMP-responsive element binding protein 3 like 1) is a metastasis suppressor that functions as a transcription factor, and in an estrogen-dependent model of rat breast cancer, it repressed the expression of genes that promote breast cancer progression and metastasis. In this report, we set out to determine the expression level of CREB3L1 across different human breast cancer subtypes and determine whether CREB3L1 functions as a metastasis suppressor, particularly in triple negative breast cancers (TNBCs). CREB3L1 expression was generally increased in luminal A, luminal B and HER2 breast cancers, but significantly reduced in a high proportion (75%) of TNBCs. Two luminal A (HCC1428, T47D) and two basal TNBC (HCC1806, HCC70) CREB3L1-deficient breast cancer cell lines were characterized as compared to their corresponding HA-CREB3L1-expressing counterparts. HA-CREB3L1 expression significantly reduced both cell migration and anchorage-independent growth in soft agar but had no impact on cell proliferation rates as compared to the CREB3L1-deficient parental cell lines. Restoration of CREB3L1 expression in HCC1806 cells was also sufficient to reduce mammary fat pad tumor formation and lung metastases in mouse xenograft models of breast cancer as compared to the parental HCC1806 cells. These results strongly support a metastasis suppressor role for CREB3L1 in human luminal A and TNBCs. Further, the ability to identify the subset of luminal A (7%) and TNBCs (75%) that are CREB3L1-deficient provides opportunities to stratify patients that would benefit from additional treatments to treat their more metastatic disease.

Homoharringtonine demonstrates a cytotoxic effect against triple-negative breast cancer cell lines and acts synergistically with paclitaxel

“…These results strongly suggest that CREB3L1 blocks angiogenesis, which is necessary for large tumors to survive and plays a key role in metastasis suppression. Additionally, re-expression of CREB3L1 in a mouse xenograft model of human TNBC similarly showed reduced tumor progression and lung metastases, as compared to the CREB3L1-deficient parental TNBC, further supporting the role of CREB3L1 as a metastasis suppressor 15 .…”

“…Overall, ~ 30% of breast cancers lack CREB3L1 expression 12 , 15 . CREB3L1-deficient breast cancers are typically the more advanced metastatic breast tumors and include ~ 75% of TNBCs 15 .…”

“…Overall, ~ 30% of breast cancers lack CREB3L1 expression 12 , 15 . CREB3L1-deficient breast cancers are typically the more advanced metastatic breast tumors and include ~ 75% of TNBCs 15 . We have shown that CREB3L1 loss directly contributes to the metastatic phenotype of breast cancer cells, using in vitro cell-based assays and animal models of breast cancer 11 , 12 , 15 .…”

“…CREB3L1-deficient breast cancers are typically the more advanced metastatic breast tumors and include ~ 75% of TNBCs 15 . We have shown that CREB3L1 loss directly contributes to the metastatic phenotype of breast cancer cells, using in vitro cell-based assays and animal models of breast cancer 11 , 12 , 15 . Re-expression of CREB3L1 in CREB3L1-deficient breast cancer cells significantly decreases metastatic properties (of growth in soft agar, migration, invasion) 11 , 15 .…”

“…We have shown that CREB3L1 loss directly contributes to the metastatic phenotype of breast cancer cells, using in vitro cell-based assays and animal models of breast cancer 11 , 12 , 15 . Re-expression of CREB3L1 in CREB3L1-deficient breast cancer cells significantly decreases metastatic properties (of growth in soft agar, migration, invasion) 11 , 15 . Consistent with these results, poorly metastatic CREB3L1-expressing cells can be converted to more metastatic phenotypes by CREB3L1 knockdown 11 .…”