Reduction of telomeric length and c-erbb-2 gene amplification in human breast cancer, fibroadenoma, and gynecomastia. Relationship to histologic grade and clinical parameters

Abstract

Background. Telomeric deletions contribute to genetic instability and may represent an important mechanism of carcinogenesis. Amplification of the c‐erbB‐2 gene has been demonstrated in breast carcinoma. The clinical significance of telomeric deletions and c‐erbB‐2 gene amplification therefore was studied in patients with breast disorders. Methods. The Southern blot analysis was used to measure telomeric length as well as the c‐erbB‐2 gene amplification of breast carcinomas, adjacent normal breast tissues, fibroadenomas, and cases of gynecomastia. Results. Significant reductions in telomeric length and concentration were observed in all breast tissues when compared to placental DNA. Mean telomeric lengths were lowest in carcinomas and fibroadenomas. There were no significant differences, however, in the telomeric lengths among tissues from patients with breast carcinomas, fibroadenomas, or gynecomastia. The degree of telomeric deletion correlated significantly with histologic grade and was most notable in Grade 3 (scirrhous) breast carcinoma. The extent of telomeric deletion reflects the histologic aggressiveness of breast carcinoma, and telomeric reduction already can be seen in the adjacent normal breast tissues from patients with breast cancer. c‐erbB‐2 gene amplification was observed in 26.8% of the patients with breast carcinoma. c‐erbB‐2 gene amplification was not observed, however, in patients with fibroadenomas or gynecomastia. The degree of telomeric deletion did not correlate with c‐erbB‐2 gene amplification, tumor size, clinical stage, steroid receptors, or prognosis. Telomeric length was shorter in lymph node‐negative tumors than in lymph node‐positive tumors. Conclusions. These findings indicate that a shorter telomere length reflects growth advantage in breast cancer tissue, and telomeric reduction may promote cancer progression. Cancer 1994; 73:2978–84.

Telomeres: Prognostic markers for solid tumors

“…42 Regardless of the methodology used, the following discussion shows that telomeres can be used as clinical biomarkers in the prognosis of solid tumors, as reported in numerous studies. [12][13][14][15][16][17][18][19][20][21][22][23][24] These studies, and their major findings, are summarized in Table I and further discussed here in detail, according to the type of solid tumors analyzed.…”

“…women die from this disease. 44 The first report describing the use of telomere length as a possible prognostic marker in breast carcinoma was published by a group led by Odagiri et al 12 In this study, Southern blot analysis was used to determine the telomere length in a cohort of 41 patients diagnosed with breast cancer and with a median follow-up time of 62.5 months. Additionally, tumor adjacent normal breast specimens were available for 22 of the patients.…”

“…15,45 At the time of their report, the authors hypothesized that telomere alterations may initiate and promote the development of malignancy. 12 In this context, Meeker et al recently observed that telomere length abnormalities represent early and prevalent genetic alterations in the multistep process of malignant transformation in several types of cancer, including breast cancer. 46 Two reports on telomeres measured as telomere DNA content, TC, one of the proxies of telomere length, 41,42 collectively indicate the prognostic potential of telomeres in breast cancer patients.…”

“…[8][9][10][11] This review summarizes the use of telomere length or its proxies, such as telomere content, as potential prognostic markers in solid tumors, a possibility that has been raised in the last decade by a number of investigators. [12][13][14][15][16][17][18][19][20][21][22][23][24] A corresponding comprehensive discussion of these promising developments has not yet been offered, in spite of the growing body of knowledge. Excluded from this discussion are numerous reports on the prognostic value of telomeres in hematological malignancies, a research area that, in contrast to solid tumors, has been addressed in more depth and previously reviewed.…”

“…For these reasons, numerous investigators have hypothesized that altered telomere length could predispose cells to possess the properties necessary to metastasize and cause recurrent disease, and thereby be a predictor of clinical outcome. [12][13][14][15][16][17][18][19][20][21][22][23][24] This concept is shown schematically in Figure 1.…”