Breast Cancer in Japanese a-Bomb Survivors

Tokunaga, Masayoshi; Land, CE; Yamamoto, Tetsuya; Asano, Masahide; Tokuoka, Shoji; Ezaki, Haruo; Nishimori, Issei

doi:10.1016/s0140-6736(82)90880-7

Cited by 31 publications

(11 citation statements)

References 16 publications

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“…The multiparous, superovulated MMTV-Neu mice demonstrated accelerated tumor development (Figure 1, 25.1 ± 5.0 weeks) compared to virgin MMTVNeu mice (34.0 ± 10.1 weeks). The acceleration of tumorigenesis by early pregnancy is consistent with the window of increased vulnerability during early reproductive age identified by chemical carcinogenic studies in rodent models (reviewed in Russo and Russo, 1998) and human epidemiological studies (Tokunaga et al, 1979;Hancock et al, 1993;Land et al, 2003). However, tumor development remained somewhat stochastic within the population, suggesting that other rate limiting steps are necessary for the formation of an ErbB2/Neu tumor.…”

Section: Resultssupporting

confidence: 70%

“…Early pregnancy accelerates ErbB2/Neu-induced mammary tumorigenesis During puberty, the developing mammary gland is particularly susceptible to carcinogenesis (Tokunaga et al, 1979;Hancock et al, 1993;Russo and Russo, 1998;Land et al, 2003). As adult pregnancy increases susceptibility to ErbB2/Neu-induced tumorigenesis, we postulated that chronic pregnancy/lactation initiated at puberty may provide a further increase in the susceptible cell population for ErbB2/Neu-induced transformation, possibly leading to synchronous tumor formation.…”

Section: Resultsmentioning

confidence: 98%

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Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors

et al. 2006

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Epidemiological studies indicate that parity enhances HER2/ErbB2/Neu-induced breast tumorigenesis. Furthermore, recent studies using multiparous, ErbB2/Neu-overexpressing mouse mammary tumor virus (MMTV-Neu) mice have shown that parity induces a population of cells that are targeted for ErbB2/Neu-induced transformation. Although parity accelerates mammary tumorigenesis, the pattern of tumor development in multiparous MMTV-Neu mice remains stochastic, suggesting that additional events are required for ErbB2/Neu to cause mammary tumors. Whether such events are genetic in nature or reflective of the dynamic hormonal control of the gland that occurs with pregnancy remains unclear. We postulated that young age at pregnancy initiation or chronic trophic maintenance of mammary epithelial cells might provide a cellular environment that significantly increases susceptibility to ErbB2/Neu-induced tumorigenesis. MMTV-Neu mice that were maintained pregnant or lactating beginning at 3 weeks of age demonstrated accelerated tumorigenesis, but this process was still stochastic, indicating that early pregnancy does not provide the requisite events of tumorigenesis. However, bitransgenic mice that were generated by breeding MMTV-Neu mice with a luteinizing hormone-overexpressing mouse model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development in the bitransgenic mice suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells that are targeted by ErbB2/Neu for transformation. Both the synchrony of tumor appearance and the ability to characterize a window of commitment by ovariectomy/palpation studies permitted microarray analysis to evaluate changes in gene expression over a defined timeline that spans the progression from normal to preneoplastic mammary tissue. These approaches led to identification of several candidate genes whose expression changes in the mammary gland with commitment to ErbB2/Neu-induced tumorigenesis, suggesting that they may either be regulated by ErbB2/Neu and/or contribute to tumor formation.

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Section: Resultssupporting

confidence: 70%

Section: Resultsmentioning

confidence: 98%

Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors

et al. 2006

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“…The risk associated with radiation continues throughout life, based on data with exposure to radiation before (Tokunaga et al, 1982) and after puberty and before menopause. Uncertainties exist about breast cancer risk from exposures after menopause (Land, 1980).…”

Section: )-mentioning

confidence: 99%

Risk of contralateral breast cancer in Denmark 1943-80

Storm¹,

Jensen²

1986

Br J Cancer

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“…The Hiroshima and Nagasaki data (Tokunaga et al, 1982) and studies on the effects of irradiation in early menarche and early pregnancy, suggest that a cell with proliferative potential, sensitive to an initial carcinogenic event, is present in larger numbers in young women (Ferguson and Anderson, 1981). Since early menopause confers a protective effect, is is assumed that some proliferation of such a cell occurs under the influence of estrogens or during cycles, thus allowing the necessary amplification of the transformed cell.…”

mentioning

confidence: 99%