Abstract
Breast cancer (BC) is the leading cause of cancer-related deaths in women. Chemoprevention of BC by using plant extracts is gaining attention. SM6Met, a well-characterized extract of Cyclopia subternata with reported selective estrogen receptor subtype activity, has shown tumor suppressive effects in a chemically induced BC model in rats, which is known to be estrogen responsive. However, there is no information on the estrogen sensitivity of the relatively new orthotopic model of LA7 cell-induced mammary tumors. In the present study, the potential chemopreventative and side-effect profile of SM6Met on LA7 cell-induced tumor growth was evaluated, as was the effects of 17β-estradiol and standard-of-care (SOC) endocrine therapies, such as tamoxifen (TAM), letrozole (LET), and fulvestrant (FUL). Tumor growth was observed in the tumor-vehicle control group until day 10 post tumor induction, which declined afterward on days 12–14. SM6Met suppressed tumor growth to the same extent as TAM, while LET, but not FUL, also showed substantial anti-tumor effects. Short-term 17β-estradiol treatment reduced tumor volume on days prior to day 10, whereas tumor promoting effects were observed during long-term treatment, which was especially evident at later time points. Marked elevation in serum markers of liver injury, which was further supported by histological evaluation, was observed in the vehicle-treated tumor control, TAM, LET, and long-term 17β-estradiol treatment groups. Alterations in the lipid profiles were also observed in the 17β-estradiol treatment groups. In contrast, SM6Met did not augment the increase in serum levels of liver injury biomarkers caused by tumor induction and no effect was observed on lipid profiles. In summary, the results from the current study demonstrate the chemopreventative effect of SM6Met on mammary tumor growth, which was comparable to that of TAM, without eliciting the negative side-effects observed with this SOC endocrine therapy. Furthermore, the results of this study also showed some responsiveness of LA7-induced tumors to estrogen and SOC endocrine therapies. Thus, this model may be useful in evaluating potential endocrine therapies for hormone responsive BC.
Highlights
Breast cancer (BC) is the most commonly diagnosed malignancy in women worldwide and a leading cause of cancer-related death in women
The newly prepared extract of SM6Met, used in the current study, contained all the compounds quantified in previously prepared SM6Met extracts at comparable concentrations, except for luteolin, which was present at a lower concentration than in previous extracts, and IMG and protocatechuic acid, which were present at higher concentrations than in previous extracts (Visser et al, 2013; Mortimer et al, 2015)
The observed tumor suppressive effect of estrogen in the current study contrasts with evidence supporting the tumor promoting effects of estrogen, this may be explained in part by the administered estrogen dose and treatment duration
Summary
Breast cancer (BC) is the most commonly diagnosed malignancy in women worldwide and a leading cause of cancer-related death in women. The goal of antihormonal therapy is to reduce ER signaling by directly antagonizing or downregulating ER or indirectly by reducing estrogen levels via inhibition of aromatase, a key enzyme in estrogen synthesis. Standard-of-care (SOC) endocrine therapies such as tamoxifen (TAM), a selective ER modulator (SERM), and fulvestrant (FUL), a selective ER down-regulator (SERD), interfere with ER signaling via direct effects on the ER. TAM acts by competitively antagonizing estrogen binding to the ER in the breast, while FUL accelerates ER degradation thereby reducing cellular ERα levels (Nathan and Schmid, 2017). Letrozole (LET), an aromatase inhibitor (AI), indirectly disrupts ER signaling by blocking the conversion of adrenal androgens to estrogen in non-ovarian tissues (Fabian, 2007)
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