MAP kinase/estrogen receptor cross-talk enhances estrogen-mediated signaling and tumor growth but does not confer tamoxifen resistance

Atanaskova, Natasha; Keshamouni, Venkateshwar G.; Krueger, Joseph S.; Schwartz, Janice A.; Miller, Fred R.; Reddy, Kaladhar B.

doi:10.1038/sj.onc.1205506

Cited by 107 publications

(97 citation statements)

References 41 publications

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“…In addition, there was an association between shifts in aromatase and in tumor pathology (neo-adjuvant course) and between changes in aromatase and tumor estrogen receptor content (adjuvant course). Several recent publications have described an 'interrelationship' between TAM exposure and MAPK activity (Donovan et al 2001, Gee et al 2001, Adeyinka et al 2002, Atanaskova et al 2002, Rabenoelina et al 2002. As demonstrated in the present investigation, MAPK activity is higher in estrogen-deprived MCF-7 cells (which reproduces results of Jeng et al 2000) as well as in the same cells treated with TAM (at least temporarily) and in established TAM-resistant cell lines (Fig.…”

Section: Discussionsupporting

confidence: 86%

New approaches to the understanding of tamoxifen action and resistance.

Lm¹,

Zheng²,

W³

et al. 2003

Endocrine-Related Cancer

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Tamoxifen (TAM) provides an effective agent for treatment of hormone-dependent breast cancer but resistance uniformly ensues upon continued use. Additional studies are required to define more precisely the mechanisms involved in development of resistance. We conducted systematic experimental and clinical studies based on the hypothesis that tumors exposed to TAM long-term may develop resistance by becoming hypersensitive to its estrogenic effects. These investigations uncovered new features of the TAM resistance (TR) phenomenon and identified possible means for its prevention and/or elimination. Initially we confirmed that TR may be divided into two subtypes, primary and acquired resistance, and that these differ by certain important characteristics including the level of the possible involvement of adaptive and genetic components. Then we distinguished at least three consequent stages of this phenomenon: stage I when TAM behaves as an antiestrogen, stage II with development of increased sensitivity to the agonistic (pro-estrogenic) properties of TAM and stage III with an adaptive increase in sensitivity to estradiol (E 2 ). During this evolutionary process, as shown in vitro, MAP kinase (MAPK) and aromatase activities increase. The time frame of the increase in MAPK activity as a rule outpaces the increase in aromatase activity during the course of the development of TR. This may occur as a response to estrogen deprivation or interruption of the process of estrogen signaling and can be one of the promoting factors of increased aromatase activation. On the other hand, the chronology of these events indicates that changes in the MAPK cascade can be more important for the early steps of the development and maintenance of the TR state. Changes in local estrogen production/sensitivity to E 2 are perhaps essential for the later steps of this phenomenon.We have explored the use of a growth factor-blocking agent to abrogate the adaptive changes in sensitivity. Farnesylthiosalicylic acid (FTS), an inhibitor of GTP-Ras binding to its membrane acceptor site, reduces the increase in the number of MCF-7 cells induced by long-term TAM treatment. It also decreases MAPK activity in TAM-treated MCF-7 cells and in established TR cell lines. Alone or in combination with letrozole (presumably, through the influence on MAPK pathway) FTS exerts moderate inhibitory effects on aromatase activity in estrogen-deprived or estrogen-exposed MCF-7 cells. Taken together, our observations suggest that FTS is a 'candidate drug' for the treatment of TR. Both the adaptive and genetic types of resistance may be amenable to this approach. Our studies underline the possible importance of starting the treatment/prevention of TR early on. From our clinical studies using immunohistochemistry, there is a rather strong rationale to include as a predisposing factor in the development of TR the increase in MAPK and aromatase activities in human primary breast tumors.In summary, data obtained during the course of this project may be considered as e...

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Section: Discussionsupporting

confidence: 86%

New approaches to the understanding of tamoxifen action and resistance.

Lm¹,

Zheng²,

W³

et al. 2003

Endocrine-Related Cancer

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“…Nevertheless, the activation of ERa due to "crosstalk" with growth factors leads to ligand-independent ERa acivation, (34,35) resulting in failure in endocrine therapy. Taking into consideration that ligand-independent activation of ERa may define a path to endocrine resistance, enhanced mechanistic insight concerning the function of its ligand-independent regulator, such as PSAP, could identify novel prognostic markers of endocrine resistance and possible targets for therapeutic intervention in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Prosaposin, a regulator of estrogen receptor alpha, promotes breast cancer growth

Sun

et al. 2012

Cancer Science

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Prosaposin, a secreted protein, is a well-known pleiotropic growth factor. Although a previous report has indicated that prosaposin is overexpressed in breast cancer cell lines, the role of prosaposin in the development of breast cancer remains to be identified. Here, we first revealed that prosaposin upregulated estrogen receptor alpha expression, nuclear translocation and transcriptional activity by western blot, immunofluorescence assay and dual luciferase reporter gene assay, respectively. Furthermore, we demonstrated prosaposin upregulated estrogen receptor alpha expression through MAPK-signaling pathway using MAPK inhibitor. Proliferation assay and tumor xenograft experiments in nude mice (n = 6 per group) further confirmed prosaposin could promote breast cancer growth significantly in vitro and in vivo. These findings suggested that prosaposin might enhance estrogen receptor alpha-mediated signaling axis and play a role in breast cancer development and progression. (Cancer Sci 2012; 103: 1820-1825 B reast cancer is the most common malignancy and the main cause of death from cancers in women.(1) The carcinogenesis of breast cancer is frequently hormone-dependent. The female sex-steroid hormone estrogen 17b-estradiol (E2) plays a prominent role in mediating the maturation, proliferation, differentiation, and influences the growth and development of breast cancer.(2) Numerous studies have indicated that E2 can induce and promote breast cancer and this process is mediated primarily by estrogen receptor alpha (ERa). (3)(4)(5) Estrogen receptor (ER) is a member of the steroid/nuclear receptor family of transcription regulators, while ERa is the predominant receptor isoform expressed in breast cancer. Approximately 70% of breast cancer patients score positive for ERa at diagnosis.(6-9) Estrogen receptor alpha promotes cell growth, metastasis and also mediates resistance to apoptosis or immunosurveillance in breast cancer. (10)(11)(12) Prosaposin (PSAP) exists as a secretory protein (70 kDa) as well as a lysosomal protein (65 kDa). The molecular weight difference depends on the post-translational glycosylation. (13) Lysosomal PSAP is the precursor of four sphingolipid activator proteins (saposin A-D) and is involved in hydrolysis of sphingolipids within lysosome.(14) Secretory PSAP is a well-known pleiotropic growth factor found in secretory body fluid, such as seminal plasma, bile, cerebrospinal fluid, human milk, (15,16) as well as neuronal surface membrane.(17) The distribution of PSAP suggests it may have some specific extracellular functions. PSAP-deficiency in human and mice is lethal. (18,19) Prosaposin knock-out mice also present with a series of developmental abnormalities in the nervous system and male reproductive organs. (18,20) Recent investigations show that PSAP could prevent cell death or apoptosis and promote cell survival. (21,22) Koochekpour et al. (23) focus on the function of PSAP in prostate cancer and find PSAP is overexpressed in prostate cancer, and also upregulates androgen receptor (...

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“…These MAPKs have been implicated in phosphorylating and activating ERs, an effect that could influence antiestrogen responsiveness (Clarke et al, 2001b;Santen et al, 2002). However, some recent studies suggest that MAPK's effects on ER do not (Atanaskova et al, 2002). Exploring the MCF7/LCC1 and MCF7/LCC9 transcriptomes by gene expression microarrays implicated several genes including IRF-1, nuclear factor-kB (NFkB), early growth response gene-1 (EGR-1), epidermal growth factor receptor (EGFR), and both tumor necrosis factor-alpha (TNFa) and its receptor TNF-R1 (Gu et al, 2002).…”

Section: Candidate Genesmentioning

confidence: 99%