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
). 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
showed a decreas
e 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.
When the WHI was initiated in 1993, their present clinical result of a reduction in breast cancer was unanticipated (7
) but is consistent nevertheless with parallel laboratory studies completed over the past 20 years. Estrogen-induced apoptosis is a plausible molecular mechanism to support an antitumor action of physiologic estrogen (8
). The key to our understanding of estrogen-induced apoptosis is the finding that breast cancer cell populations adapt to estrogen deprivation, but these populations are dynamic, and resistance to estrogen deprivation evolves over time (5 years). This evolution of resistance to estrogen deprivation causes a reconfiguration of cellular survival pathways, which in turn exposes a vulnerability of breast cancer cell survival. Physiologic estrogen causes
apoptosis and does not act as a survival signal (8
We will weigh the laboratory and clinical evidence to support the proposition that physiologic estrogen can cause apoptosis in breast cancer cells following long-term estrogen deprivation. Our objective is to make a case based on scientific observations to support our proposition that nascent breast cancer cells could have the same apoptotic response to ERT after estrogen deprivation caused by menopause. We will present the evidence in chronological order (Box 1
Box 1. Cumulative evidence to support low dose estrogen-induced apoptosis in long term estrogen deprived nascent breast cancer
- Historical use of estrogens to treat breast cancer.
- Physiologic estrogen as an antitumor agent in SERM resistant breast cancer models in vivo.
- Estrogen-induced apoptosis in estrogen deprived ER-positive cell lines in vitro.
- A current evaluation of estrogen to treat acquired antihormone resistance in metastatic breast cancer.
- The extrapolation of the concept that physiologic estrogen kills breast cancer cells to adjuvant antihormone therapy.