In Vitro Effects of Combining Genistein with Aromatase Inhibitors: Concerns Regarding Its Consumption during Breast Cancer Treatment.

INTRODUCTION: The third-generation of aromatase inhibitors (AIs)-Exemestane (Exe), Letrozole (Let), and Anastrozole (Ana)-is the main therapeutic approach applied for estrogen receptor-positive (ER+) breast cancer (BC), the most common neoplasm in women worldwide. Despite their success, the development of resistance limits their efficacy. Genistein (G), a phytoestrogen present in soybean, has promising anticancer properties in ER+ BC cells, even when combined with anticancer drugs. Thus, the potential beneficial effects of combining G with AIs were investigated in sensitive (MCF7-aro) and resistant (LTEDaro) BC cells. METHODS: The effects on cell proliferation and expression of aromatase, ERα/ERß, and AR receptors were evaluated. RESULTS: Unlike the combination of G with Ana or Let, which negatively affects the Ais' therapeutic efficacy, G enhanced the anticancer properties of the steroidal AI Exe, increasing the antiproliferative effect and apoptosis relative to Exe. The hormone targets studied were not affected by this combination when compared with Exe. CONCLUSIONS: This is the first in vitro study that highlights the potential benefit of G as an adjuvant therapy with Exe, emphasizing, however, that soy derivatives widely used in the diet or applied as auxiliary medicines may increase the risk of adverse interactions with nonsteroidal AIs used in therapy.

Effects of PI3K inhibition in AI-resistant breast cancer cell lines: autophagy, apoptosis, and cell cycle progression.

INTRODUCTION: Breast cancer is the leading cause of cancer death in women. The aromatase inhibitors (AIs), Anastrozole (Ana), Letrozole (Let), and Exemestane (Exe) are a first-line treatment option for estrogen receptor-positive (ER+) breast tumors, in postmenopausal women. Nevertheless, the development of acquired resistance to this therapy is a major drawback. The involvement of PI3K in resistance, through activation of the PI3K/AKT/mTOR survival pathway or through a cytoprotective autophagic process, is widely described. MATERIALS AND METHODS: The involvement of autophagy in response to Ana and Let treatments and the effects of the combination of BYL-719, a PI3K inhibitor, with AIs were explored in AI-resistant breast cancer cell lines (LTEDaro, AnaR, LetR, and ExeR). RESULTS: We demonstrate that Ana and Let treatments do not promote autophagy in resistant breast cancer cells, contrary to Exe. Moreover, the combinations of BYL-719 with AIs decrease cell viability by different mechanisms by nonsteroidal vs. steroidal AIs. The combination of BYL-719 with Ana or Let induced cell cycle arrest while the combination with Exe promoted cell cycle arrest and apoptosis. In addition, BYL-719 decreased AnaR, LetR, and ExeR cell viability in a dose- and time-dependent manner, being more effective in the ExeR cell line. This decrease was further exacerbated by ICI 182,780. CONCLUSION: These results corroborate the lack of cross-resistance between AIs verified in the clinic, excluding autophagy as a mechanism of resistance to Ana or Let and supporting the ongoing clinical trials combining BYL-719 with AIs.

Differential biological effects of aromatase inhibitors: Apoptosis, autophagy, senescence and modulation of the hormonal status in breast cancer cells.

Estrogen receptor-positive (ER+) breast carcinomas are the most common subtype, corresponding to 60% of the cases in premenopausal and 75% in postmenopausal women. The third-generation of aromatase inhibitors (AIs), the non-steroidal Anastrozole (Ana) and Letrozole (Let) and the steroidal Exemestane (Exe), are considered a first-line endocrine therapy for postmenopausal women. Despite their clinical success, the development of resistance is the major setback in clinical practice. Nevertheless, the lack of cross-resistance between AIs hints that these drugs may act through distinct mechanisms. Therefore, this work studied the different effects induced by AIs on biological processes, such as cell proliferation, death, autophagy and senescence. Moreover, their effects on the regulation of the hormonal environment were also explored. The non-steroidal AIs induce senescence, through increased YPEL3 expression, on aromatase-overexpressing breast cancer cells (MCF-7aro), whereas Exe promotes a cytoprotective autophagy, thus blocking senescence induction. In addition, in a hormone-enriched environment, the non-steroidal AIs prevent estrogen signaling, despite up-regulating the estrogen receptor alpha (ERα), while Exe down-regulates ERα and maintains its activation. In these conditions, all AIs up-regulate the androgen receptor (AR) which blocks EGR3 transcription in Exe-treated cells. On the other hand, in hormone-depleted conditions, a crosstalk between AR and ERα occurs, enhancing the estrogenic effects of Exe. This indicates that Exe modulates both ERα and AR, while Ana and Let act as pure AIs. Thus, this study highlights the potential clinical benefit of combining AR antagonists with Exe and discourages the sequential use of Exe as second-line therapy in postmenopausal breast cancer.