mechanism of her2+ bc's relative insensitivity to radiation therapy elucidated

[Lani]

Int J Oncol. 2009 Nov;35(5):1141-9.
The involvement of HER2 and p53 status in the regulation of telomerase in irradiated breast cancer cells.

Papanikolaou V, Iliopoulos D, Dimou I, Dubos S, Tsougos I, Theodorou K, Kitsiou-Tzeli S, Tsezou A.
Laboratory of Cytogenetics and Molecular Genetics, Medical School, University of Thessaly, 41110 Larissa, Greece.
Cancer cell characteristics may play a pivotal role in the response to therapy by activating or deactivating different molecular pathways. In the present study, we investigated the implication of breast cancer cell features, such as HER2 and p53 in the activation of telomerase upon exposure to ionizing radiation. Telomerase is among the most important cancer biomarkers, conferring to tumor cells unlimited proliferative capacity, increased survival potential and resistance to several types of cellular stress. We investigated possible mechanisms regulating telomerase in six irradiated breast cancer cell lines (MCF-7, MCF-7/HER2, MDA-MB-231, SK-BR-3, BT-474 and HBL-100) differing in their HER2, p53 and ERalpha status. hTERT mRNA expression was evaluated by real-time PCR and telomerase activity by the TRAP assay. HER2, c-myc, p53 and p21 protein levels were evaluated by Western blotting. Silencing of hTERT and HER2 was achieved by small interfering RNA technology. Chromatin immunoprecipitation was used to evaluate H3 histone acetylation status, as well as myc/mad/max and p53 transcription factors interaction with the hTERT promoter. Our results showed for the first time, that only HER2-positive cells, independently of their p53 status, upregulated hTERT/telomerase, while knockdown of hTERT increased radio-sensitivity. Knockdown of HER2 also led to increased radio-sensitivity and downregulation of hTERT/telomerase. We also demonstrated that c-myc and mad1 regulate hTERT expression in all irradiated breast cancer cells. We conclude, for the first time, that HER2 phenotype upregulates hTERT through c-myc activation and confers radio-resistance to breast cancer cells.
PMID: 19787269

[bejuce]

Interesting article. I had not heard about HER-2+ cancers being resistant to radiation before. Can you point out any other studies that show this to be the case? I'm wondering why my radiation oncologist has not mentioned this to me...

Thanks!

[Lani]

J Huazhong Univ Sci Technolog Med Sci. 2009 Jun;29(3):350-3. Epub 2009 Jun 10. Links

Induction of ERBB2 nuclear transport after radiation in breast cancer cells.

Luo B, Yu S, Zhuang L, Xia S, Zhao Z, Rong L.
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China, luobotongji@yahoo.com.cn.
The ERBB2 nuclear transport in breast cancer cell lines after radiation and its possible role in radiation tolerance were observed. Confocal microscopy and Western blotting were applied to detect the nuclear ERBB2 expression after radiation in breast carcinomas cells. And the effects of Herceptin, AG825 and Cisplatin on the expression of nuclear ERBB2 were investigated. Survival fractions were also observed. After radiation, compared with control group, confocal microscopy and Western blot revealed that the expression of nuclear ERBB2 was increased in breast cancer cells time-dependently. Herceptin, and AG825 could significantly inhibit the radiation-induced nuclear ERBB2 expression, and decrease survival fractions. Cisplatin also induced the nuclear ERBB2 expression in breast cancer cells with high ERBB2 expression. It was concluded that radiation could induce ERBB2 nuclear transport, and nuclear ERBB2 may correlate with radiation resistance in breast cancer cells with high ERBB2 expression.
PMID: 19513620

[Chelee]

I find this very interesting also!

Chelee

[Lani]

her2 linked to local control failure with radiation therapy mentioned in this article below

Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):1173-80. Epub 2008 Dec 6. Links
Hypofractionated and accelerated radiotherapy with subcutaneous amifostine cytoprotection as short adjuvant regimen after breast-conserving surgery: interim report.

Koukourakis MI, Tsoutsou PG, Abatzoglou IM, Sismanidou K, Giatromanolaki A, Sivridis E.
Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis, Greece. targ@her.forthnet.gr
PURPOSE: Short radiotherapy schedules might be more convenient for patients and overloaded radiotherapy departments, provided late toxicity is not increased. We evaluated the efficacy and toxicity of a hypofractionated and highly accelerated radiotherapy regimen supported with cytoprotection provided by amifostine in breast cancer patients treated with breast-conserving surgery. METHODS AND MATERIALS: A total of 92 patients received 12 consecutive fractions of radiotherapy (3.5 Gy/fraction for 10 fractions) to the breast and/or axillary/supraclavicular area and 4 Gy/fraction for 2 fractions to the tumor bed). Amifostine at a dose of 1,000 mg/d was administered subcutaneously. The follow-up of patients was 30-60 months (median, 39). RESULTS: Using a dose individualization algorithm, 77.1% of patients received 1,000 mg and 16.3% received 750 mg of amifostine daily. Of the 92 patients, 13% interrupted amifostine because of fever/rash symptoms. Acute Grade 2 breast toxicity developed in 6.5% of patients receiving 1,000 mg of amifostine compared with 46.6% of the rest of the patients (p < .0001). The incidence of Grade 2 late sequelae was less frequent in the high amifostine dose group (3.2% vs. 6.6%; p = NS). Grade 1 lung fibrosis was infrequent (3.3%). The in-field relapse rate was 3.3%, and an additional 2.2% of patients developed a relapse in the nonirradiated supraclavicular area. c-erbB-2 overexpression was linked to local control failure (p = .01). Distant metastasis appeared in 13% of patients, and this was marginally related to more advanced T/N stage (p = .06). CONCLUSION: Within a minimal follow-up of 2.5 years after therapy, hypofractionated and accelerated radiotherapy with subcutaneous amifostine cytoprotection has proved a well-tolerated and effective regimen. Longer follow-up is required to assess the long-term late sequelae.
PMID: 19058920

[Lani]

Radiat Res. 2009 Jan;171(1):9-21. Links
NF-kappaB-mediated HER2 overexpression in radiation-adaptive resistance.

Cao N, Li S, Wang Z, Ahmed KM, Degnan ME, Fan M, Dynlacht JR, Li JJ.
Division of Molecular Radiobiology and Graduate Program of Radiation and Cancer Biology, Purdue University School of Health Sciences, West Lafayette, IN 47907, USA.
The molecular mechanisms governing acquired tumor resistance during radiotherapy remain to be elucidated. In breast cancer patients, overexpression of HER2 (human epidermal growth factor receptor 2) is correlated with aggressive tumor growth and increased recurrence. In the present study, we demonstrate that HER2 expression can be induced by radiation in breast cancer cells with a low basal level of HER2. Furthermore, HER2-postive tumors occur at a much higher frequency in recurrent invasive breast cancer (59%) compared to the primary tumors (41%). Interestingly, NF-kappaB is required for radiation-induced HER2 transactivation. HER2 was found to be co-activated with basal and radiation-induced NF-kappaB activity in radioresistant but not radiosensitive breast cancer cell lines after long-term radiation exposure, indicating that NF-kappaB-mediated HER2 overexpression is involved in radiation-induced repopulation in heterogeneous tumors. Finally, we found that inhibition of HER2 resensitizes the resistant cell lines to radiation. Since HER2 is shown to activate NF-kappaB, our data suggest a loop-like HER2-NF-kappaB-HER2 pathway in radiation-induced adaptive resistance in breast cancer cells.
PMID: 19138055