Roles of CCN5 in regulating progression and therapeutic sensitivity of breast cancer

Abstract

Breast cancer is one of the deadliest malignancies worldwide and also in the United States. Patients with triple negative breast cancer (TNBC), where the cancer cells do not express nuclear hormone receptors and human epidermal growth factor receptor 2 (HER2), have worse survival rate compared to the patients with luminal subtypes of cancer. Here, we have shown that Cysteine-rich 61-Connective Tissue Growth Factor-nephroblastoma-overexpressed 5 (CCN5) induces growth arrest of TNBC cells in-vitro and in xenograft tumors. Our studies show that after being secreted into the extracellular matrix, CCN5 binds to the α6β1 integrins of the cells leading to inhibition of the PI3K-AKT signaling pathway. This leads to stabilization and nuclear localization of FOXO3A resulting in transcriptional activation of the cyclin-dependent kinase inhibitor P27KIP1. Also, we found that the CCN5-induced PI3K-AKT inactivation leads to stabilization and nuclear accumulation of P27KIP1 resulting in cell cycle arrest of TNBC cells. Next, we have shown that CCN5 protein can induce expression of estrogen receptor-α (ER-α) in mammary epithelial cells. We found that mammary epithelium-specific overexpression of CCN5 in transgenic mice leads to an increase in ER-α expression and that this impact of CCN5 is not restricted to the normal cells. CCN5 treatment leads to an expression of functional ER-α in the TNBC cells, both in-vitro and in xenograft models, and sensitizes these cells to tamoxifen, commonly used for endocrine therapies. Mechanistically, transcriptional activation of ER-α by CCN5 is also mediated by FOXO3A stabilization via PI3K-AKT inhibition. Lack of ER-α expression in TNBC cells or loss of ER-α activation after endocrine treatment of luminal cancers makes these breast cancer cells resistant to tamoxifen and other endocrine therapies. Evidently, CCN5-mediated restoration of ER-α and its downstream signaling cascades renders the TNBC cells sensitive to tamoxifen. As these tumors mostly lack CCN5 expression, we anticipate that restoration of CCN5 expression might be able to provide breakthroughs in the treatment of these tumors. Finally, we discuss the effects of CCN5 expression on yet another aggressive breast cancer subtype, characterized by HER2 overexpression. Mammary-specific expression of CCN5 in HER2 overexpressing mice delays tumor progression significantly and reduces the tumor burden. Initial observations indicate that CCN5 induces expression of P16INK4A and P19ARF, resulting in cell cycle arrest of the tumor cells. Collectively, these studies suggest that CCN5 restoration can be beneficial for the better management of breast cancer progression.