Abstract
Triple receptor-negative breast cancers (TNBCs) generally have poor prognoses because of the loss of therapeutic targets. As lysophosphatidic acid (LPA) receptor signaling has been shown to affect breast cancer initiation and progression, we try to evaluate the potential roles of LPA receptors in TNBCs. We examined mRNA and protein expressions of LPA receptors 1-3, using quantitative real-time PCR and immunohistochemical analyses in normal (n = 37), benign disease (n = 55), and breast cancer tissues (n = 82). Carcinomas expressed higher levels of LPA2 and LPA3 mRNAs (0.17 ± 0.070 and 0.05 ± 0.023, respectively) than did normal breast tissue (0.13 ± 0.072 and 0.02 ± 0.002, respectively). Enhanced immunohistochemical staining for LPA2 and LPA3 protein was also consistently observed in carcinomas. The LPA3 overexpression was associated with lymph node metastases, and absence of estrogen receptor, progesterone receptors, and human epidermal growth factor receptor 2 expression. TNBC tissues and cell lines showed the highest LPA3 expression compared with luminal-type A and B breast cancers. Suppression of LPA3 by shRNA did not influence cell growth in breast cancer cells. However, the migration and invasion of TNBC cells were significantly inhibited by LPA3-shRNA or inhibitor, which had no or less effect on normal and non-TNBC breast cells. In conclusion, our data indicated that the expression of LPA receptor 3 was increased in human TNBCs and is associated with tumor metastatic ability, and this implies that LPA3 is a potential therapeutic target for the treatment of TNBCs.
Highlights
Breast cancer is the most commonly diagnosed cancer, and the leading cause of cancer-related deaths, in women worldwide [1]
lysophosphatidic acid (LPA) receptors are expressed by normal mammary epithelial cells, with aberrant expression occurring during breast cancer initiation and progression [18]
We found abnormal expression of LPA receptors in mammary carcinomas, and that LPA2 and LPA3 expression was enhanced in breast cancer compared with normal breast and benign-disease tissues, the expression level of LPA1 was not significantly different between each subgroup
Summary
Breast cancer is the most commonly diagnosed cancer, and the leading cause of cancer-related deaths, in women worldwide [1]. Breast cancers have many effective treatment options, fewer targeted therapies are available for triple receptor-negative breast cancers (TNBCs). Some progress has been made in classifying TNBCs into several distinct subtypes using gene expression profiling analyses, and some kinases and agents were identified as potential druggable targets [3, Clin Exp Med (2015) 15:371–380. At least six LPA receptors (LPA1–6) are currently identified, and their emerging roles in tumorigenesis have been demonstrated both in vitro and in vivo [7]. Overexpression of LPA1 and LPA2 was readily observed in breast cancers with redundant mediation functions in multiple endogenous LPA responses, including cancer cell growth, metastasis, angiogenesis, and chemoresistance [8, 11,12,13]. Previous published data showed that LPA3 was higher expression in poorly differentiated breast cancers than well-differentiated tumors [14, 15], which suggests that LPA3 contributes to breast cancer progression
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