It is widely held that estrogen can be carcinogenic in breast tissue (1) and is the “fuel for the fire” to stimulate the growth of estrogen receptor (ER)–positive breast cancer cells (2). This knowledge, supported by an enormous body of laboratory data, provides the conceptual basis for the successful development of antihormonal strategies to treat breast cancer (3). Selective ER modulators (SERMs), e.g. tamoxifen, block estrogen-stimulated tumor growth at the ER, and aromatase inhibitors prevent peripheral estrogen synthesis in postmenopausal patients, thereby creating estrogen deprivation to stop tumor growth (3). The successful treatment strategy for breast cancer with SERMs was subsequently translated into reducing the risk of breast cancer in high-risk women. SERMs are available to reduce the incidence of breast cancer in pre- and postmenopausal (tamoxifen) or postmenopausal (raloxifene) women (4–6). As predicted by the mechanism of action of SERMs as anticancer agents, only ER-positive breast cancer is reduced. In practice, preventing estrogen action prevents breast tumor initiation and growth. Paradoxically, the recent analysis of estrogen replacement therapy (ERT) in the Women’s Health Initiative (WHI) double-blind, placebo-controlled randomized trial in 10,739 postmenopausal women with a prior hysterectomy (ages 50–79; ref. 7) actually showed a decrease in invasive breast cancer, which was sustained for 5 years after ERT was stopped. This result seems to run counter to the perceived wisdom of the role of estrogen in breast carcinogenesis, was significant in women of all ages, and was similar in every age group.

The application of high-dose estrogen therapy for the treatment of metastatic breast cancer was the first use of a chemical therapy to treat any cancer successfully (9). Estrogen therapy became the standard of care to treat metastatic breast cancer in postmenopausal patients until the introduction of tamoxifen (late 1970s in the U.S.), a nonsteroidal antiestrogen (10). Tamoxifen became the “gold standard” for the treatment of ER-positive (estrogen stimulated) breast cancer for the next 20 years. Estrogen was all but abandoned as a treatment option, but Ingle et al. completed a provocative trial of tamoxifen versus the synthetic estrogen diethylstilbestrol (DES; high-dose) in metastatic breast cancer (11). Responses were equivalent with fewer side effects with tamoxifen, but a re-analysis years later demonstrated that survival was significantly improved with DES (12).

In the 1980s, the first athymic animal models of tamoxifen-induced antihormone resistance were reported, but the acquired resistance surfaced within 2 years as tamoxifen-stimulated growth (2). This replicated the use of tamoxifen in the treatment of metastatic ER-positive breast cancer but did not explain the astonishing success of 5 years of adjuvant tamoxifen therapy in reducing recurrences by 50% and mortality by 30%. Most important, the gains obtained during therapy are maintained (and mortality further reduced) for the next 15 years. We were missing a vital clue about the evolution of antihormone resistance in micrometastatic breast cancer.

Song and co-workers (20) first showed in cell culture that high concentrations of estrogen could induce cellular apoptosis directly through a FAS/FASL pathway. However, the discovery that physiologic concentrations of estradiol could induce apoptosis (21) in both cell culture and animal models was the advance pertinent to the clinical observation that ERT reduces the incidence of breast cancer in postmenopausal women (7). This is now a consistent experimental observation with new knowledge emerging about the molecular mechanisms of estrogen-induced apoptosis. Figure 1 summarizes much of the current data on molecular mechanisms of estrogen-induced apoptosis, the topic of a forthcoming mini-review in Cancer Prevention Research later this year.

The result from the WHI Trial of ERT in hysterectomized women (7), which showed a sustained reduction in the incidence of breast cancer, provides additional evidence that the strategy to decipher the mechanism of physiologic estrogen to induce apoptosis (8, 25, 26) has significance for both treatment and prevention. Indeed, the idea that a woman’s own estrogen was responsible for enhanced survivorship by causing apoptosis of the appropriately prepared and vulnerable micrometastases (16) followed the completion of long-term adjuvant tamoxifen therapy and now is incorporated into the Study of Letrozole Extension (SOLE) Trial. This extended adjuvant antihormone treatment study (Figure 2) is addressing the question of whether regular drug holidays will decrease recurrence rates compared with continuous therapy. For initial safety reasons, a women’s own estrogen during the drug holiday is hypothesized to be adequate as an apoptotic trigger because rigorous prior antihormone therapy will have selected vulnerable cell populations as the waiting target. Subsequent trials may have to use ERT for a few weeks to trigger apoptosis.