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Mechanistic Progress of Estrogen-induced Apoptosis in Estrogen-deprived Breast Cancer Cells | OMICS International
ISSN: 2157-7013
Journal of Cell Science & Therapy

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Mechanistic Progress of Estrogen-induced Apoptosis in Estrogen-deprived Breast Cancer Cells

Shuqiao Chai1,2and Ping Fan2*
1McLean High School, 1633 Davidson Road, McLean, VA 22102, USA
2Department of Breast Medical Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1354, Houston, TX 77030, USA
Corresponding Author : Ping Fan
MD PhD, Department of Breast Medical Oncology
MD Anderson Cancer Center, 1515 Holcombe Blvd
Unit 1354, Houston, TX 77030, USA
Tel: 713-792-2121
E-mail: [email protected]
Received: July 03, 2015 Accepted: July 29, 2015 Published: July 31, 2015
Citation: Chai S, Fan P (2015) Mechanistic Progress of Estrogen-induced Apoptosis in Estrogen-deprived Breast Cancer Cells. J Cell Sci Ther 6:218. doi:10.4172/2187-7013.1000218
Copyright: © 2015 Chai S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The laboratory discovery of estrogen-induced apoptosis has been translated to treat antihormone resistant patients and to reduce the incidence of breast cancer in postmenopausal hysterectomized women with estrogen replacement therapy (ERT). The key step is the selection pressure exerted by long-term antiestrogen therapy or over 5 years of menopause to specific breast cancer cell populations that will be vulnerable to estrogen-induced apoptosis. However, the mechanisms underlying estrogen-induced apoptosis are currently unclear. At the cellular level, estrogen-induced apoptosis is dependent upon the estrogen receptor (ER), which can be completely blocked by antiestrogen ICI 182,780 or 4-hydroxytamoxifen (4-OHT). Knockdown of ER alpha, but not ER beta, through specific small interfering RNAs effectively blocks estrogen-induced apoptosis, indicating that the ER alpha subtype participates in apoptosis. Further examinations demonstrate that estrogen-induced apoptosis is due to accumulation of endoplasmic reticulum stress, inflammatory responses, and oxidative stress, which, in turn, activate the intrinsic mitochondrial pathway and the extrinsic death receptor pathway to complete the process. This contrasts with paclitaxel, which causes G2 arrest with immediate apoptosis. These stress responses are modulated by glucocorticoids and the c-Src inhibitor to block estrogen-induced apoptosis, but the mechanism for estrogen action is through a genomic pathway rather than a non-genomic pathway. In the nucleus, estrogen activates classic ERE-regulated endogenous genes, but the ERE transcriptional pathway does not directly participate in the estrogen-induced apoptosis in vitro or in vivo. Simultaneously, estrogen activates a non-classic transcriptional pathway involving the interaction of ER with transcription factors such as activator protein-1 (AP-1), which may regulate proliferation, stress responses, or apoptosis. Investigation of how AP-1 modulates the stress responses to trigger estrogen-induced apoptosis will ultimately uncover the mechanisms underlying estrogen-induced apoptosis.

Estrogen; Estrogen receptor; Estrogen-induced apoptosis; Breast cancer
Estrogen (E2) plays a pivotal role in the development and progression of breast cancers [1]. As a result, blockade of E2 signals through either aromatase inhibitors (AIs) or selective estrogen receptor modulators (SERMs) is an important therapeutic strategy to treat or prevent estrogen receptor (ER) positive breast cancers [2]. These endocrine therapies have significantly improved breast cancer survival [3-6]. Paradoxically, long-term endocrine therapy generates selection pressure for cell populations that evolve from acquired resistance to eventually expose a vulnerability that is expressed as E2-induced apoptosis in vitro [7,8] and in vivo [9-11]. All of these laboratory data with MCF-7 cells provide the scientific rationale for the subsequent finding that high dose (30 mg daily) or low dose (6 mg daily) E2 produces a 30% clinical benefit rate in patients failing aromatase inhibitor therapy [12]. Further, E2-induced apoptosis has been used to explain lower incidences of breast cancer and mortality of postmenopausal women in their 60s undergoing E2 replacement therapy (ERT) [13]. A recent study addresses the hypothesis that women taking traditional hormone replacement therapy (HRT) comprising of E2 plus medroxyprogesterone acetate (MPA) may have an increased risk of breast cancer, as MPA may act as a glucocorticoid and block E2-induced apoptosis in E2-deprived breast cancer cells [14]. All of these observations indicate the clinical implications of E2- induced apoptosis. However, mechanisms of E2-induced apoptosis are currently unclear. This review will focus on the progress of mechanistic discoveries in E2-induced apoptosis in breast cancer cells.
Evolution of Estrogen-induced Apoptosis is Selected by Antiestrogen Pressure
Laboratory findings with the MCF-7 breast cancer cell line grown in athymic mice first described tamoxifen-stimulated growth as a new mechanism of drug resistance to a therapeutic intervention [15]. However, discovery that re-transplantation of tamoxifen-stimulated tumors into successive generations of athymic mice over 5 years results in the selection of a resistant tumor cell population that is killed by physiological levels of E2 [9-11], which results in the new biology of E2- induced apoptosis [16].
A similar story has also occurred over the past 20 years with the development of models to study antihormone resistance to aromatase inhibtors (AIs). The discovery that breast cancer cells, in particular MCF-7 cells, have been grown routinely in the medium with phenol red [17] that contains estrogenic activity revolutionized options to solve the question of what happens to hormone-responsive cells once starved of E2 i.e. AI therapy. Wild-type MCF-7 cells grow with radioimmunologically undetectable levels of E2 (Figure 1), whereas long- term E2-deprived MCF-7 cells, MCF-7:5C undergo apoptosis by E2 (Figure 1). Thus, both E2 deprivation [7,8] and SERMs produce the same selective pressure on MCF-7 cells [9-11] to create selective cellular populations vulnerable to E2-induced apoptosis [18]. A period of 5-10 years is required to accomplish the described selection process [19]. The apoptotic action of E2 provides a new clinical treatment strategy for breast cancer patients following exhaustive antihormonal therapy [12,20,21]
Estrogen induces a delayed apoptosis in breast cancer cells
The estrogen receptor (ER) is the initial trigger for E2 to induce apoptosis since antiestrogens ICI 182,780 and 4-hydroxytamoxifen (4- OHT) completely block apoptosis triggered by E2 [22]. Contradictory to the traditional apoptosis mechanism caused by cytotoxic chemotherapy, E2-induced apoptotic cells simultaneously undergo proliferation with an increased S phase of the cell cycle, resulting in an increased cell number [22-25]. The possibility that apoptotic impairment can be rescued by antiestrogen is a unique feature of E2-induced apoptosis, which differs from the rapid (12 hour) chemotherapy-induced cytotoxic apoptosis [24]. E2 exerts a dual function on E2-deprived cells, with both initial proliferation and subsequent apoptosis [22]. In other words, there is not any detected apoptotic change in the first 24 hours after E2 treatment [22], which gives researchers a possibility to reverse E2-induced apoptosis by antiestrogen within 24 hours [24]. Activation of apoptotic genes appears after 48 hours treatment with E2, and reaches a peak after 72 hours [22]. Our observations also indicate that insulin-like growth factor-1 receptor (IGF-1R)/phosphoinositide 3-kinase (PI3K) is a dominant growth driver after E2 treatment in two E2-deprived breast cancer cells [23,26], which activates Akt to promote cell growth [23, 26]. These data suggest that the higher rate of proliferation by E2 might activate other pathways to trigger apoptosis.
Estrogen induces apoptosis through nuclear estrogen receptor alpha (ERα)
The original target site of E2-induced apoptosis is ER alpha (ERα) [22,27], which can be completely blocked by the knockdown of ERα, but not ERβ, through small interfering RNA (siRNA) [28]. Oncogene c-Src functions as an important downstream signal of ERα in MCF- 7:5C cells, which is activated by E2 and demonstrates multiple levels of association with ERα [22]. A well-known function of c-Src is that it mediates the non-genomic pathway of E2 in E2-deprived breast cancer cells [22]. However, E2-induced apoptosis is not through a nongenomic pathway [22]. This conclusion is supported by the evidence that synthetic macromolecules, estrogen-dendrimer conjugates (EDCs) that remain outside the nucleus [29] activate the non-genomic pathway while are unable to activate the genomic pathway, thereby not inducing apoptosis in MCF-7:5C cells [22]. All of these observations indicate that nuclear ERα plays an important role in E2-induced apoptosis [22]. In the nucleus, E2 activates classic ERE-regulated endogenous genes in MCF-7:5C cells [22,27], but the ERE transcriptional pathway does not directly participate in the E2-induced apoptosis in vitro [22] or in vivo [30]. Our global gene array [27] data suggest that E2 signaling can occur through a non-classic transcriptional pathway involving the interaction of ER with transcription factors such as activator protein-1 (AP-1), which may regulate proliferation, stress responses, or apoptosis [31].
Accumulation of stresses activates estrogen-induced apoptosis
The endoplasmic reticulum and mitochondria are two key organelles involved in E2-induced apoptosis [22]. The sensors of unfolded protein response (UPR) and the oxidative stress sensor HMOX1 are activated by E2 as initial adaptive responses in an attempt to sustain a balance in cell survival. A cross-talk exists between the endoplasmic reticulum and mitochondria to activate apoptosis cascades during E2- induced apoptosis (Figure 2). UPR initially occurs after a few hours of treatment with E2 [22]. Three sensors of endoplasmic reticulum stress, protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring protein 1 alpha (IRE1α), and activating transcription factor 6 (ATF6) are activated by E2 [22,27]. PERK attenuates protein translation, which has been confirmed as an important inducer for E2-induced apoptosis [22]; On the other hand, ATF-6 and IRE1 increase endoplasmic reticulum folding capacity by up-regulating the endoplasmic reticulum chaperones and the endoplasmic reticulumassociated protein degradation (ERAD) machinery [32,33]. The initial aim of UPR is to restore the normal function of the cell; however, if the damage is too severe to repair, the UPR ultimately initiates cell death through activation of the apoptotic pathway [34]. Compelling evidence suggests that E2 induces apoptosis through accumulation of stress responses, including endoplasmic reticulum stress, oxidative stress, and inflammatory stress [22,23,27]. Glucocorticoid and the c-Src inhibitor are able to modulate stress responses to block E2-induced apoptosis [14,22]. Currently, it is under investigation how E2 activates the nuclear AP-1 complex to modulate the stress and apoptosis in E2-deprived breast cancer cells (Figure 2).
Conclusion and Future Direction
Despite the limitations of ER positive breast cancer cell lines [35], long-term estrogen-deprived MCF-7 cell models [7,8] are invaluable tools to uncover the mechanisms underlying E2-induced apoptosis (Figure 2). This scientific rationale has been utilized in clinical trials which have confirmed that E2 can reduce the incidence of breast cancer in postmenopausal women [12,13]. Laboratory evidence for modification of apoptosis by E2 through the glucocorticoid-like action of MPA provides an important rationale to change the traditional HRT strategy [14]. Principles have emerged for understanding and applying physiological E2 therapy appropriately by targeting the correct patient populations [36,37]. However, new findings reflect that the rapid plasticity of hormone resistance occurs as a response to selection pressure [14,22,26], indicating that there is still long way to translate such treatment into bedside practice.


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