Reduction in apoptosis relative to mitosis in histologically normal epithelium accompanies fibrocystic change and carcinoma of the premenopausal human breast

Allan, David J.; Howell, Anthony; Roberts, Stephen A; Williams, Gerrard T.; Watson, Robert J.; Coyne, John; Clarke, Robert B.; Laidlaw, Ian; Potten, Christopher S

doi:10.1002/path.1711670106

Cited by 116 publications

(58 citation statements)

References 12 publications

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“…Furthermore, we have noted Al to be closely related to the nuclear grade of the DCIS lesions (Figure 2). Whereas Bodis et al (1996) failed to find any evidence of apoptosis in grade 1 DCIS lesions, we have found the median Al in nuclear grade 1 DCIS lesions to be 0.35%, a value similar to that described in normal breast epithelium taken from women undergoing a breast biopsy for fibroadenoma [0.33% and 0.35% by Allan et al (1992) and Potten et al (1988) respectively]. It is unlikely that apoptosis is present.in normal epithelium yet totally absent in malignancy (DCIS), and our finding of genetically programmed cell death in grade 1 DCIS probably represents the 'background' apoptosis seen in normal breast tissue.…”

Section: Apoptotic and Proliferative Indicessupporting

confidence: 75%

“…Cells undergoing apoptotic death display characteristic morphological features and are removed by phagocytosis in the absence of any inflammatory response, thereby permitting cell death without damage to adjacent cells (Schwartzman and Cidlowski, 1993;Kerr et al, 1994). Apoptosis is believed to act as the counterbalance to proliferation (mitosis) and is a critical factor in tissue homeostasis (Potten, 1992). Dysregulation of the apoptotic process may therefore play a crucial role in oncogenesis.…”

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confidence: 99%

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Evidence of significant apoptosis in poorly differentiated ductal carcinoma in situ of the breast

Gandhi¹,

Pa²,

Knox³

et al. 1998

Br J Cancer

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Summary Following breast-conserving surgery for ductal carcinoma in situ (DCIS), the presence of comedo necrosis reportedly predicts for higher rates of post-operative recurrence. To examine the role of programmed cell death (apoptosis) in the aetiology of the cell death described as comedo necrosis, we studied 58 DCIS samples, using light microscopy, for morphological evidence of apoptotic cell death. The percentage of apoptotic cells (apoptotic index, Al) was compared between DCIS with and without evidence of 'comedo necrosis' and related to the immunohistochemical expression of the anti-apoptosis gene bcl-2, mitotic index (Ml), the cellular proliferation antigen Ki67, nuclear grade and oestrogen receptor (ER) status. Al was significantly higher in DCIS samples displaying high-grade comedo necrosis than in lowgrade non-comedo samples: median Al = 1.60% (range 0.84-2.89%) and 0.45% (0.1-1.31%) respectively (P < 0.001). Increasing nuclear grade correlated positively with Al (P < 0.001) and negatively with bcl-2 expression (P = 0.003). Bcl-2 correlated negatively with Al (P = 0.019) and strongly with ER immunoreactivity (P < 0.001). Cellular proliferation markers (Ml and Ki67 immunostaining) correlated strongly with Al and were higher in comedo lesions and tumours of high nuclear grade (P < 0.001 in all cases). Thus, apoptosis contributes significantly to the cell death described in ER-negative, high-grade DCIS in which a high proliferative rate is associated with a high apoptotic rate. It is likely that dysregulation of proliferation/apoptosis control mechanisms accounts for the more malignant features typical of ER negative comedo DCIS.

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Section: Apoptotic and Proliferative Indicessupporting

confidence: 75%

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confidence: 99%

Evidence of significant apoptosis in poorly differentiated ductal carcinoma in situ of the breast

Gandhi¹,

Pa²,

Knox³

et al. 1998

Br J Cancer

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“…In a previous study, we have shown breast cancer cells exhibit reduced apoptosis compared to normal breast epithelium (Shao et al, 1996). Investigators in another study reported reduced breast epithelial cell apoptosis in association with fibrocystic disease and an increased risk of carcinoma (Allan et al, 1992). Other investigators have shown that the inhibition of apoptosis is linked to tumour promotion (Tomei et al, 1988).…”

Section: Discussionmentioning

confidence: 75%

Prognostic role of p27Kip1 and apoptosis in human breast cancer

Shen

et al. 1999

Br J Cancer

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Human breast carcinoma is biologically heterogeneous, and its clinical course may vary from an indolent slowly progressive one to a course associated with rapid progression and metastatic spread. It is important to establish prognostic factors which will define subgroups of patients with low vs high risk of recurrence so as to better define the need for additional therapy. Additional characterization of the molecular make-up of breast cancer phenotypes should provide important insights into the biology of breast cancer. In the present study, we investigated apoptosis, expression of p27 Kip1 and p53 retrospectively in 181 human breast cancer specimens. In addition, their relevance to the biological behaviour of breast cancer was examined. Our studies found a significant association among high histological grade, high p53, low apoptosis and low p27. Our results also demonstrated that, in human breast cancer, low levels of p27 and apoptotic index (AI) strongly correlated with the presence of lymph node metastasis and decreased patient survival. In node-negative patients, however, p27 also had prognostic value for relapse-free and overall survival in multivariate analysis. Furthermore p27 and AI had predictive value for the benefits of chemotherapy. These latter observations should prompt prospective randomized studies designed to investigate the predictive role of p27 and AI in determining who should receive chemotherapy in node-negative patients. © 1999 Cancer Research Campaign

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“…64 These findings of reduced apoptosis are relevant since decreased mammary epithelial apoptosis is associated with an increased risk of fibrocystic changes and the development of carcinoma in premenopausal women. 65 We are currently breeding our MMTV-IGF-II transgenic mice with mice that overexpress the neu oncogene to examine whether IGF-II-mediated inhibition of epithelial apoptosis augments neu-induced mammary tumorigenesis.…”

Section: The Antiapoptotic Property Of Igf-ii May Underlie Its Tumorimentioning

confidence: 99%

Inhibition of mammary epithelial apoptosis and sustained phosphorylation of Akt/PKB in MMTV-IGF-II transgenic mice

et al. 2001

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IGF-II is a growth factor implicated in human cancers and animal tumor models. While the mitogenic properties of IGF-II are well documented, its ability to suppress apoptosis in vivo has never been proven. We generated independent MMTV-IGF-II transgenic mice to examine the control of epithelial apoptosis at the morphological, cellular and molecular levels during the physiological event of postlactation mammary involution. Transgenic IGF-II expression was achieved in mammary epithelium and increased IGF-II bioactivity was confirmed by phosphorylation of the insulin receptor substrate-1, a signaling molecule downstream of the type I IGF receptor. IGF-II overexpression induced a delay in mammary involution, as evident by increased mammary gland to body weight ratios and persistence of both functionally intact lobulo-alveoli and mammary epithelial cellularity. The delayed mammary involution resulted from a significant reduction in mammary epithelial apoptosis, and not from increased epithelial proliferation. Recombinant IGF-II pellets implanted into involuting mammary glands of wild-type mice provided further evidence that IGF-II protein inhibited local epithelial apoptosis. At the molecular level, phosphorylated Akt/PKB, but not Erk1 or Erk2, persisted in IGF-II overexpressors and temporally correlated with reduced epithelial apoptosis. Levels of the phosphatase PTEN were unaltered in the transgenic tissue suggesting that the maintenance of Akt/PKB phosphorylation resulted from sustained phosphorylation rather than altered dephosphorylation of PIP-3. Together, this data reveal that IGF-II inhibits apoptosis in vivo and this effect correlates with prolonged phosphorylation of Akt/PKB Cell Death and Differentiation (2001) 8, 16 ± 29.

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Reduction in apoptosis relative to mitosis in histologically normal epithelium accompanies fibrocystic change and carcinoma of the premenopausal human breast

Cited by 116 publications

References 12 publications

Evidence of significant apoptosis in poorly differentiated ductal carcinoma in situ of the breast

Evidence of significant apoptosis in poorly differentiated ductal carcinoma in situ of the breast

Prognostic role of p27Kip1 and apoptosis in human breast cancer

Inhibition of mammary epithelial apoptosis and sustained phosphorylation of Akt/PKB in MMTV-IGF-II transgenic mice

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