Abstract
Simple SummaryEstrogen is responsible for tumor progression, and blocking its synthesis is effective in certain breast cancers. Therefore, the aim of this study is to determine the effect of letrozole (anti-aromatase) and STX-64 (anti-sulfatase) in canine and human inflammatory breast cancer cell lines and xenografts. The results reveal that letrozole blocks estrogen synthesis, reducing tumor progression. However, STX-64 increases estradiol synthesis, increasing tumor progression. In summary, letrozole may be an effective treatment for canine and human inflammatory breast cancer.Blocking estrogen synthesis by inhibitors of estrogen synthesis is a widely used therapy against estrogen receptor-positive tumors. However, these therapies are less effective in negative expression tumors. Therefore, this study determined the effectiveness of anti-aromatase and anti-sulfatase therapies in canine and human inflammatory breast cancer. Cell cultures and xenografts from IPC-366 and SUM149 were treated with different doses of letrozole (anti-aromatase) and STX-64 (anti-sulfatase), in order to observe their effectiveness in terms of cell proliferation, tumor progression, and the appearance of metastases and hormonal profiles. The results revealed that both treatments are effective in vitro since they reduce cell proliferation and decrease the secreted estrogen levels. In xenograft mice, while treatment with letrozole reduces tumor progression by 30–40%, STX-64 increases tumor progression by 20%. The hormonal results obtained determined that STX-64 produced an increase in circulating and intratumoral levels of estradiol, which led to an increase in tumor progression. However, letrozole was able to block estrogen synthesis by decreasing the levels of circulating and intratumoral estrogen and thus slowing down tumor progression. In conclusion, letrozole can be an effective treatment for canine and human inflammatory breast cancer. The knowledge of the hormonal profile of breast tumors reflects useful information on the effectiveness of different endocrine treatments.
Highlights
Estrogen has long been described as a key regulator of breast cancer growth and differentiation
STX-64 in vitro treatment resulted in a slight augmentation of cell viability at 48 h, it decreased at 72 h (Figure 1B)
These treatments present limitations since their administration can produce important side effects and does not exempt the risk of recurrences [1]. Such endocrine therapies are known to be insensitive on triple negative breast cancers, new approaches have denoted that these patients could benefit from these treatments, as compounds such as tamoxifen could act through an estrogen receptor (ER)-independent pathway [4]
Summary
Estrogen has long been described as a key regulator of breast cancer growth and differentiation. 75% of breast cancers are estrogen receptor (ER)-positive [1]. Treatments against the synthesis or action of estrogen have been extensively used. Two principal pathways are implicated in the estrogen formation in breast cancer tissues: the aromatase pathway, mediated by the enzyme CYP19-aromatase, which transforms androgen into estrogen, and the sulfatase pathway, which converts estrone into estrone sulfate by the enzyme sulfotransferase [2]. Estrogen may arise from aromatase activity in extraovarian body sites, such as subcutaneous adipose tissue and skin, and may reach breast cancer in an endocrine manner. An increase of local concentrations of estrogen may result from aromatase overexpression within the tumor tissue [1,3]
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