Tamoxifen up-regulates c-erbB-2 expression in oestrogen-responsive breast cancer cells in vitro

doi:10.1016/S0959-8049(05)80045-0

European Journal of Cancer

Volume 28, Issues 2–3, February–March 1992, Pages 318-321

https://doi.org/10.1016/S0959-8049(05)80045-0 Get rights and content

Expression of the c-erbB-2 proto-oncogene is inhibited by oestrogens in oestrogen-responsive human breast cancer cells, at both mRNA and protein level. Here we report that, where the regulation of c-erbB-2 is concerned, tamoxifen displays a full anti-oestrogenic activity, enhancing the expression of c-erbB-2 in oestrogen receptor-positive cells cultured with untreated fetal calf serum or reversing the inhibitory effect of added oestrogens. Meanwhile, tamoxifen strongly inhibited cell growth. Tamoxifen was inactive on both c-erbB-2 expression and growth of oestrogen receptor-negative cells. These results may have important implications to explain occasional failure of tamoxifen therapy in oestrogen receptor-positive breast cancers.

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Citation Excerpt :
Except for modulating estrogen, TAM also induces cell cycle arrest in breast cancer [45]. In estrogen-responsive breast cancer, it promotes transcription of c-erbB-2, an oncogene related to breast cancer aggression and drug resistance [46]. The details of these mechanisms and targets are shown in Table 2.
Proliferating cancer cells exhibit metabolic alterations and specific nutritional needs for adapting to their rapid growth. These changes include using aerobic glycolysis, lipid metabolic disorder, and irregular protein degradation. It may be useful to target metabolic abnormalities for cancer chemoprevention. Epidemiological and mechanism-related studies have indicated that many FDA-approved anti-metabolic drugs decrease tumor risk, inhibit tumor growth, or enhance the effect of chemotherapeutic drugs. Drugs targeting nutrient metabolism have fewer side effects with long-term use compared to chemotherapeutic drugs. The characteristics of these drugs make them promising candidates for cancer chemoprevention. Here, we summarize recent discoveries of the chemo-preventive effects of drugs targeting nutrient metabolic pathways and discuss future applications and challenges. Understanding the effects and mechanisms of anti-metabolic drugs in cancer has important implications for exploring strategies for cancer chemoprevention.
Modulation of Δ<sup>9</sup>-tetrahydrocannabinol-induced MCF-7 breast cancer cell growth by cyclooxygenase and aromatase
2009, Toxicology
Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), a major constituent of marijuana, has been shown to stimulate the growth of MCF-7 breast cancer cells through cannabinoid receptor-independent signaling [Takeda, S., Yamaori, S., Motoya, E., Matsunaga, T., Kimura, T., Yamamoto, I., Watanabe, K., 2008. Δ⁹-Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling. Toxicology 245, 141–146]. Although the growth of MCF-7 cells is known to be stimulated by 17β-estradiol (E₂), the interaction of Δ⁹-THC and E₂ in MCF-7 cell growth is not fully clarified so far. In the present study, by using E₂-sensitive MCF-7 cells that have expressed cyclooxygenase-2 (COX-2) and cytochrome P450 19 (aromatase), we studied whether or not COX-2 and aromatase are involved in Δ⁹-THC-mediated MCF-7 cell proliferation. It was shown that Δ⁹-THC-induced MCF-7 cell growth was inhibited by COX-2 inhibitors and was stimulated by arachidonic acid (a COX substrate). However, the growth of MCF-7 cells induced by Δ⁹-THC was not stimulated by PGE₂, and the expression of aromatase was not affected by COX-2 inhibitors, arachidonic acid, and PGE₂, suggesting that there is a disconnection between COX-2 (PGE₂) and aromatase in Δ⁹-THC-mediated MCF-7 cell proliferation. On the other hand, Δ⁹-THC-induced MCF-7 cell growth was elevated by two kinds of aromatase inhibitors. Taken together with the evidence that Δ⁹-THC-induced MCF-7 cell proliferation was interfered with testosterone (an aromatase substrate) and exogenously provided E₂, it is suggested that (1) the growth stimulatory effects of Δ⁹-THC are mediated by the product(s) of COX-2 except for PGE₂, (2) the action of Δ⁹-THC is modulated by E₂, and (3) COX-2 and aromatase are individually engaged in the proliferation of MCF-7 cells induced by Δ⁹-THC.
Δ<sup>9</sup>-Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling
2008, Toxicology
We recently reported that Δ⁹-tetrahydrocannabinol (Δ⁹-THC) has the ability to stimulate the proliferation of human breast carcinoma MCF-7 cells. However, the mechanism of action remains to be clarified. The present study focused on the relationship between receptor expression and the effects of Δ⁹-THC on cell proliferation. RT-PCR analysis demonstrated that there was no detectable expression of CB receptors in MCF-7 cells. In accordance with this, no effects of cannabinoid 1/2 (CB1/2) receptor antagonists and pertussis toxin on cell proliferation were observed. Although MCF-7 cell proliferation is suggested to be suppressed by Δ⁹-THC in the presence of CB receptors, it was revealed that Δ⁹-THC could exert upregulation of living cells in the absence of the receptors. Interestingly, Δ⁹-THC upregulated human epithelial growth factor receptor type 2 (HER2) expression, which is known to be a predictive factor of human breast cancer and is able to stimulate cancer cells as well as MCF-7 cells. Actinomycin D-treatment interfered with the upregulation of HER2 and cell proliferation by cannabinoid. Taken together, these studies suggest that, in the absence of CB receptors, Δ⁹-THC can stimulate the proliferation of MCF-7 cells by modulating, at least in part, HER2 transcription.
Bifunctional effect of resveratrol on the expression of ErbB2 in human breast cancer cell
2006, Cancer Letters
Citation Excerpt :
ERE (estrogen response element)-reporter gene analysis showed that resveratrol significantly increased the ERE-reporter activity in a concentration-dependent manner (Fig. 1B). It has been reported that anti-estrogen enhances the expression of ErbB2 in breast cancer cells [23]. Furthermore, resveratrol acts as an anti-estrogen in some types of cells such as endometrial adenocarcinoma cells [24].
This study evaluated the effect of resveratrol on the expression of ErbB2 in a human breast cancer cell line, MCF-7. Low concentrations of resveratrol (1–10 μM) reduced the basal expression level of ErbB2 in MCF-7 cells cultured in an estrogen-free medium. When cells were cultured in a medium containing estrogen, resveratrol increased the ErbB2 protein levels in a dose-dependent manner. Resveratrol increased the luciferase reporter gene activity in cells transfected with the −756 bp flanking region of the human erbB2 gene. Resveratrol increased the nuclear levels of AP-2α and AP-2γ, and the induction of the luciferase reporter gene by resveratrol was inhibited by a mutation of two AP-2 binding sites in the promoter region of the human erbB2 gene. Blocking the ERK, p38 kinase or PI3-kinase activity had no effect on the resveratrol-inducible transactivation of the erbB2 gene and the ErbB2 expression level.
Using aromatase inhibitors in the neoadjuvant setting: Evolution or revolution?
2005, Cancer Treatment Reviews
Despite improvements in the management of patients with early breast cancer, the prognosis for women with locally advanced breast cancer (LABC) remains poor. The potential goals of neoadjuvant treatment for this disease include downsizing tumours to allow breast conservation as well as the possibility of improving survival rates. Neoadjuvant treatment was initially dominated by chemotherapy, which increased rates of breast conserving surgery, but to date has demonstrated no survival benefit over standard adjuvant chemotherapy. With recent advances in endocrine therapy, and rapid and routine assessment of predictive factors of response such as estrogen (ER), progesterone (PR) and Her2 nu receptor status, endocrine therapy has come to the forefront of research investigating a neoadjuvant alternative to chemotherapy.
Early studies of neoadjuvant endocrine therapy mainly evaluated the role of tamoxifen in the treatment of elderly postmenopausal women with LABC who were unselected for ER/PR status and were unsuitable for either surgery or chemotherapy. Response rates in these patients were found to be inferior to those traditionally obtained from trials with neoadjuvant chemotherapy.
Paralleling the superiority that third-generation aromatase inhibitors have shown over tamoxifen in the metastatic and adjuvant settings however, AIs have also demonstrated superiority in the neoadjuvant setting. Recent studies have shown response rates for neoadjuvant treatment with aromatase inhibitors in carefully selected hormone receptor positive patients to be comparable to those seen with neoadjuvant chemotherapy. This is particularly important as hormone receptor positive tumours have repeatedly been shown to have lower response rates to neoadjuvant chemotherapy than hormone receptor negative tumours.
Neoadjuvant endocrine treatment with aromatase inhibitors has therefore evolved from being an experimental effort to palliate women with LABC unsuitable for surgery or chemotherapy, to representing a viable and possibly preferred alternative for postmenopausal women with hormone receptor positive large tumours or LABC. Further benefits of neoadjuvant trials include allowing the study of predictive biomarkers of disease in order to provide insight into therapy resistance and sensitivity, and identifying promising systemic therapies for additional testing in larger adjuvant trials.
Combining trastuzumab (Herceptin®) with hormonal therapy in breast cancer: What can be expected and why?
2003, Annals of Oncology
Citation Excerpt :
It has been demonstrated in vitro that estrogen down-regulates HER2 expression and that anti-estrogen produces partial reversal of this effect in MCF-7 breast cancer cells [48]. The promoter of the HER2 gene contains an estrogen response element and estrogen has been shown to suppress the transcription of HER2 [49], while tamoxifen up-regulates the transcription of HER2 [50]. Thus, the estrogen response element seems to negatively regulate HER2 transcription under the influence of estrogen binding to ER [51].
Hormonal therapy and the humanised anti-HER2 monoclonal antibody trastuzumab (Herceptin®) represent one of the oldest and one of the newest treatment modalities for breast cancer, respectively. Recent data have suggested that HER2 overexpression is associated with resistance to hormonal therapy and there is considerable preclinical evidence to support the existence of interaction or ‘cross talk’ between HER2 and estrogen-receptor (ER) signalling pathways in breast cancer. Preclinical data also demonstrate that adding trastuzumab to hormonal therapy results in greater antitumour activity than either agent alone. The existence of an inverse relationship between ER expression and HER2 overexpression has also been well established clinically. Thus, a range of clinical trials are now ongoing to determine whether the addition of trastuzumab to hormonal therapy will provide breast cancer patients with benefits in clinical practice. This review describes the rationale for these trials and discusses the potential of therapeutic regimens combining trastuzumab with hormonal therapy.

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European Journal of Cancer

References (24)

Structure and inducible regulation of the human c-erbB-2/neu promoter

J Biol Chem

Single-step inducation of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene

Cell

Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene

Cell

c-erbB-2 protein expression in node-negative breast cancer

Ann Oncol

p185, a product of the neu proto-oncogene, is a receptor-like protein associated with tyrosine kinase activity

Mol Cell Biol

Similarity of protein encoded by the human c-erbB-2 gene to epidermal growth factor receptor

Nature

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

Science

c-erbB-2 oncogene as a prognostic marker in breast cancer

Br J Cancer

Inhibition of c-erbB-2 oncogene expression by estrogens in human breast cancer cells

Oncogene

Hormonal modulation of HER-2/neu protooncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines

Cancer Res

Expression of the c-erbB-2 protein in normal and transformed cells

Int J Cancer

Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family

Nucleic Acids Res

Cited by (62)

Targeting nutrient metabolism with FDA-approved drugs for cancer chemoprevention: Drugs and mechanisms

Modulation of Δ<sup>9</sup>-tetrahydrocannabinol-induced MCF-7 breast cancer cell growth by cyclooxygenase and aromatase

Δ<sup>9</sup>-Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling

Bifunctional effect of resveratrol on the expression of ErbB2 in human breast cancer cell

Using aromatase inhibitors in the neoadjuvant setting: Evolution or revolution?

Combining trastuzumab (Herceptin®) with hormonal therapy in breast cancer: What can be expected and why?

PaperTamoxifen up-regulates c-erbB-2 expression in oestrogen-responsive breast cancer cells in vitro

J Biol Chem

Cell

Cell

Ann Oncol

p185, a product of the neu proto-oncogene, is a receptor-like protein associated with tyrosine kinase activity

Mol Cell Biol

Similarity of protein encoded by the human c-erbB-2 gene to epidermal growth factor receptor

Nature

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

Science

c-erbB-2 oncogene as a prognostic marker in breast cancer

Br J Cancer

Inhibition of c-erbB-2 oncogene expression by estrogens in human breast cancer cells

Oncogene

Hormonal modulation of HER-2/neu protooncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines

Cancer Res

Expression of the c-erbB-2 protein in normal and transformed cells

Int J Cancer

Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family

Nucleic Acids Res

Paper
Tamoxifen up-regulates c-erbB-2 expression in oestrogen-responsive breast cancer cells in vitro