Preclinical modeling of endocrine response and resistance

Abstract

The authors developed a breast cancer intratumoral aromatase model system to compare the antitumor efficacy of several aromatase inhibitors (AIs) and antiestrogens (AEs). Although the AI letrozole caused sustained growth inhibition, tumors eventually began to grow, even when treatment was maintained. For the current study, the mechanisms of resistance to letrozole during the course of treatment were investigated. Estrogen receptor alpha (ER-alpha) levels decreased below control levels in letrozole-resistant tumors. The decrease was simultaneous to an increase in phosphorylation of ER-alpha and an unaltered expression of progesterone receptor (PgR). Expression levels of HER-2, activated (phosphorylated) SHC-adaptor protein (p-Shc), growth factor receptor-bound protein 2 (Grb-2), p-Raf, phosphorylated mitogen-activated protein kinase kinase 1/2 (p-Mekl/2), and phosphorylated mitogen-activated protein kinase (p-MAPK) were increased. When cells isolated from letrozole-resistant tumors (LTLTCa cells) were treated with inhibitors of the HER-2 signaling pathway, ER-alpha expression and estradiol-stimulated transactivation was restored. The HER-2 blocker trastuzumab also restored the sensitivity of LTLTCa cells to AIs and AEs. These findings suggested that there is crosstalk between ER and HER-2 signaling. To prevent activation of the HER-2 pathway and resistance to AIs, mice were treated with a combination of AIs and the ER down-regulator fulvestrant. There was no increase in HER-2 or p-MAPK expression, and tumor growth was inhibited significantly. When trastuzumab was added to unresponsive tumors under letrozole treatment, it significantly inhibited tumors growth compared with switching to trastuzumab alone. However, the trastuzumab plus letrozole combination was more effective than letrozole alone only in refractory breast tumors. These results suggested that blocking both ER and HER-2 signaling may delay the development of resistance to AIs in patients with recurrent breast cancer.

Lapatinib Restores Hormone Sensitivity with Differential Effects on Estrogen Receptor Signaling in Cell Models of Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer with Acquired Endocrine Resistance

“…The human epidermal GFR-2 (HER2) is significantly overexpressed, or amplified in 10% of early ERα+ breast cancers and has been associated with poor prognosis and de novo resistance to both tamoxifen and aromatase inhibitors (4)(5)(6)(7). Importantly, preclinical models have shown that the development of acquired endocrine resistance can be associated with more modest adaptive upregulation in growth factor signaling pathways (8)(9)(10)(11).…”

Combination of Anastrozole with Fulvestrant in the Intratumoral Aromatase Xenograft Model

“…The positive effect of the combination of anastrozole plus fulvestrant in sequence or continuously is associated with downregulation of a refractory phenotype represented by IGF-IR, AKT, MAPK, p-MAPK, mTOR, p-mTOR, and ERa expression. The combination of letrozole and fulvestrant also repressed HER2 and p-MAPK expression in the tumors treated with the combination therapy compared with tumors treated with letrozole alone (48).…”

Current NCI-sponsored Cooperative Group trials of endocrine therapies in breast cancer

“…Dr. Brodie has developed the ovariectomized nude mouse with estrogen-dependent MCF-7 breast cancer cells that have undergone transfection with the human aromatase gene to evaluate AI effects. 8 In this model, the combination of tamoxifen and either nonsteroidal AI, anastrozole, or letrozole, had no improved efficacy over tamoxifen alone 9 and correctly predicted the result seen in the Arimidex or Tamoxifen Alone or in Combination (ATAC) trial. 10 Most recently, this model has been used to evaluate combinations versus sequencing of endocrine and targeted therapies.…”

“…This activation may result in overexpression of human epidermal growth-factor receptor-2 neu (HER-2 neu). 8 Strategies to overcome endocrine resistance would involve the use of agents directed against the activated growth-factor pathway. Trastuzumab, which targets against HER-2 neu, may be helpful in overcoming endocrine resistance.…”