The Consequences of Exhaustive Antiestrogen Therapy in Breast Cancer: Estrogen-Induced Tumor Cell Death

Abstract

Forty years ago, the endocrine treatment for breast cancer was a last resort at palliation before the disease overwhelmed the patient (1). Ovarian ablation was the treatment of choice for the premenopausal patient, whereas either adrenalectomy or, paradoxically, high-dose synthetic estrogen therapy were used for treatment in postmenopausal patients. A reduction or an excess of estrogen provoked objective responses in one out of three women. Unfortunately, there was no way of predicting who would respond to endocrine ablation, and because so few patients responded there was no enthusiasm for developing new endocrine agents. All hopes for a cure for breast cancer turned to appropriate combinations of cytotoxic chemotherapy. Today tamoxifen, a nonsteroidal antiestrogen (2), has proven to be effective in all stages of premenopausal and postmenopausal breast cancer, and several new endocrine strategies, including aromatase inhibitors, luteinizing-hormone releasing hormone (LHRH) superagonists, and a pure antiestrogen (fulvestrant), are now available for breast cancer treatment. Additionally, tamoxifen and raloxifene, a related compound, are used to reduce the risk of breast cancer and osteoporosis, respectively, in high-risk groups (3). Hormonal modulation and strategies to prevent the actions of estrogen in the breast are ubiquitous. However, with successful changes in treatment strategies comes the consequence of change. This minireview will describe the current strategies for the treatment and prevention of breast cancer and present emerging new concepts about the consequences of exhaustive antiestrogen treatment on therapeutic resistance.

Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells

“…It was reported that high doses of estrogen could inhibit the progression of breast cancer in some patients with exhaustive antiestrogen therapy. [5]. Further studies confirmed that estrogen induced growth suppression in endocrine resistant breast cancer was due to apoptosis [24, 25].…”

“…On the other hand, ectopic expression of ERα in ERα negative mammary epithelial cells was shown to inhibit their proliferation [2, 3] and proliferating normal mammary epithelial cells are often ER negative [4]. In fact, high doses of synthetic estrogen were shown to inhibit tumor growth in patients with ER positive breast cancer [5]. These observations suggest that estrogen signaling appears growth-inhibitory in mammary epithelial cells.…”

Estrogens exert a rapid apoptotic action in anterior pituitary cells

“…A delicate balance between cell survival and cell death governed by ER is now well recognized (22). It has been proposed that the E 2 -ER complex interprets its natural environment to decide cell survival or death (39). In addition to the well-known proliferative effects of estrogens on lactotropes, recent evidence has shown that estrogens also trigger antiproliferative responses in anterior pituitary cells (19,23) and sensitize them to apoptotic signals (8,16,58).…”

Contribution of α2-adrenoceptors to the mitogenic effect of catecholestrogen in human breast cancer MCF-7 cells

“…This compound causes ubiquitination and destruction of the ER-ICI 182780 complex, resulting in downregulation of the ER [32,33]. In every case, a partial reversion of the mitogenic action of catecholestrogen was observed by this compound, suggesting that part of this action is mediated either directly or indirectly by ERs.…”