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Thyronamine regulation of TAAR1 expression in breast cancer cells and investigation of its influence on viability and migration.

ABSTRACT:

Objectives

A correlation exists between breast cancer and thyroid disorders, which are common in elderly women. Thyroid hormones are degraded into trace amines, which can bind to the G-protein-coupled receptor trace amine-associated receptor 1 (TAAR1) and thereby activate it. The transformation of thyroid hormones into trace amines is carried out by the ornithine decarboxylase. Previously, we showed that TAAR1 overexpression (IRS ?6) was associated with a significantly longer OS in primary breast cancer patients during a long-term follow-up of up to 14 years. Aim of the present study was to analyze the regulation of TAAR1 in breast cancer cell lines and the influence of triiodothyronine (T₃), thyronamines, and tetraiodothyroacetic acid (Tetrac) on the expression of TAAR1 in breast cancer cells.

Methods

The effect of T₃, thyronamines, and Tetrac on the expression of TAAR1 in breast cancer cell lines MCF-7 and T47D was analyzed via PCR and Western blot. A MTT assay was performed to test the metabolic cell viability. A scratch assay was performed to analyze cell migration.

Results

Stimulation of MCF-7 cells with 10 nM 3-iodothyronamine (T₁AM) significantly increased TAAR1 protein expression (P=0.008). In T47D cells, TAAR1 expression was significantly upregulated after the addition of 10 µg/mL estradiol to 10 nM T₁AM (P=0.008). A significant (P=0.028) reduction in MCF-7 cell viability through the incubation with T₁AM could be detected. Cell migration of MCF cells was significantly reduced through incubation with 10 nM T₁AM.

Conclusion

A significant upregulation of TAAR1 induced by stimulation with T₁AM may be a sign for an increased decarboxylation of thyroid hormones in breast cancer cells. In addition, there seems to be an influence of estradiol for the T₁AM-induced upregulation of TAAR1 in T47D cells. TAAR1-related cell transduction mechanisms seem to be an interesting target for endocrine treatment options of breast cancer patients.

SUBMITTER: Tremmel E

PROVIDER: S-EPMC6385785 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Breast cancer accounts for nearly a quarter of all cancers in women worldwide, and more than 90% of women diagnosed with breast cancer undergo mastectomy or breast-conserving surgery. Retrospective clinical studies have suggested that use of regional anesthesia leads to improved patient outcomes. Laboratory studies have reported that breast cancer cells are inhibited by some local anesthetics at millimolar concentration. Here, we present a comprehensive analysis of the effects of six common local anesthetics on two human breast cancer cell lines. We used concentrations ranging from those corresponding to plasma levels during regional block by local anesthetic (plasma concentration) to those corresponding to direct infiltration of local anesthetic. METHODS:Human breast cancer cell lines, MDA-MB-231 and MCF7, were incubated with each of six local anesthetics (lidocaine, mepivacaine, ropivacaine, bupivacaine, levobupivacaine, and chloroprocaine) (10 ?M ~?10 mM) for 6 to 72 h. Assays for cell viability, cytotoxicity, migration, and cell cycle were performed. RESULTS:High concentrations (>?1 mM) of local anesthetics applied to either MDA-MB-231 or MCF7 cells for 48 h significantly inhibited cell viability and induced cytotoxicity. At plasma concentrations (~?10 ?M) for 72 h, none of the local anesthetics affected cell viability or migration in either cell line. However, at 10?×?plasma concentrations, 72-h exposure to bupivacaine, levobupivacaine or chloroprocaine inhibited the viability of MDA-MB-231 cells by >?40% (p?<?0.001). Levobupivacaine also inhibited the viability of MCF7 cells by 50% (p?<?0.001). None of the local anesthetics affected the viability of a non-cancerous breast cell line, MCF10A. MDA-MB-231 cell migration was inhibited by 10?×?plasma concentrations of levobupivacaine, ropivacaine or chloroprocaine and MCF7 cell migration was inhibited by mepivacaine and levobupivacaine (p?<?0.05). Cell cycle analysis showed that the local anesthetics arrest MDA-MB-231 cells in the S phase at both 1?×?and 10?×?plasma concentrations. CONCLUSIONS:Local anesthetics at high concentrations significantly inhibited breast cancer cell survival. At 10?×?plasma concentrations, the effect of local anesthetics on cancer cell viability and migration depended on the exposure time, specific local anesthetic, specific measurement endpoint and specific cell line.