Irradiation of Juvenile, but not Adult, Mammary Gland Increases Stem Cell Self-Renewal and Estrogen Receptor Negative Tumors

Tang, Jonathan; Fernandez‐Garcia, Ignacio; Vijayakumar, Sangeetha; Martinez-Ruis, Haydeliz; Illa-Bochaca, Irineu; Nguyen, David H.; Mao, Jian‐Hua; Costes, Sylvain V.; Barcellos-Hoff, Mary Helen

doi:10.1002/stem.1533

Cited by 49 publications

(55 citation statements)

References 50 publications

(88 reference statements)

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“…Genes decreased in MaSC signature were also decreased in K18-IHPsi (P ¼ 7 Â 10 À5 ), consistent with their ER-negative status, and likely reflecting the MaSC as cell of origin (36). This signature was not evident in K14/18-IHPsi, suggesting that host irradiation has tumorspecific engagement ( Supplementary Fig.…”

Section: Z-scorementioning

confidence: 53%

“…Our prior studies show that irradiating hosts with either sparsely or densely ionizing radiation shifted the dominant tumor type from ER-positive to ER-negative (30,36). Most (62%, n ¼ 15/24) tumors arising in sham-irradiated mice were ER-positive, compared with 33% (n ¼ 4/12) in g-irradiated hosts and 43% (n ¼ 15/35) in Si-irradiated (combined dose groups) hosts.…”

Section: Resultsmentioning

confidence: 96%

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Densely Ionizing Radiation Acts via the Microenvironment to Promote Aggressive Trp53-Null Mammary Carcinomas

et al. 2014

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Densely ionizing radiation, which is present in the space radiation environment and used in radiation oncology, has potentially greater carcinogenic effect compared with sparsely ionizing radiation that is prevalent on earth. Here, we used a radiation chimera in which mice were exposed to densely ionizing 350 MeV/amu Si-particles, g-radiation, or sham-irradiated and transplanted 3 days later with syngeneic Trp53-null mammary fragments. Trp53-null tumors arising in mice irradiated with Si-particles had a shorter median time to appearance and grew faster once detected compared with those in sham-irradiated or g-irradiated mice. Tumors were further classified by markers keratin 8/18 (K18, KRT18), keratin 14 (K14, KRT14) and estrogen receptor (ER, ESR1), and expression profiling. Most tumors arising in sham-irradiated hosts were comprised of both K18-and K14-positive cells (K14/ 18) while those tumors arising in irradiated hosts were mostly K18. Keratin staining was significantly associated with ER status: K14/18 tumors were predominantly ER-positive, whereas K18 tumors were predominantly ERnegative. Genes differentially expressed in K18 tumors compared with K14/18 tumor were associated with ERBB2 and KRAS, metastasis, and loss of E-cadherin. Consistent with this, K18 tumors tended to grow faster and be more metastatic than K14/18 tumors, however, K18 tumors in particle-irradiated mice grew significantly larger and were more metastatic compared with sham-irradiated mice. An expression profile that distinguished K18 tumors arising in particle-irradiated mice compared with sham-irradiated mice was enriched in mammary stem cell, stroma, and Notch signaling genes. These data suggest that carcinogenic effects of densely ionizing radiation are mediated by the microenvironment, which elicits more aggressive tumors compared with similar tumors arising in sham-irradiated hosts. Cancer Res; 74(23); 7137-48. Ó2014 AACR.

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Section: Z-scorementioning

confidence: 53%

Section: Resultsmentioning

confidence: 96%

Densely Ionizing Radiation Acts via the Microenvironment to Promote Aggressive Trp53-Null Mammary Carcinomas

et al. 2014

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“…The tumor growth rate of tumors arising from transplantation to adults was comparable to that observed in previous experiments(23). Moreover the difference of tumor growth rate was replicated in cohort of mice transplanted as adults versus juveniles in an independent study(28). Mitotic figures that included the spectrum of condensed chromosome states (Figure 2B) were quantified in high-powered fields of view (n=10) per hematoxylin and eosin (H&E)-stained tumor.…”

Section: Resultsmentioning

confidence: 95%

Distinct Luminal-Type Mammary Carcinomas Arise from Orthotopic Trp53-Null Mammary Transplantation of Juvenile versus Adult Mice

et al. 2014

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Age and physiological status, like menopause, are risk factors for breast cancer. Less clear is what factors influence the diversity of breast cancer. In this study, we investigated the effect of host age on the distribution of tumor subtypes in mouse mammary chimera consisting of wild-type hosts and Trp53 nullizygous epithelium, which undergoes a high rate of neoplastic transformation. Wild-type mammary glands cleared of endogenous epithelium at 3 weeks of age were subsequently implanted during puberty (5 weeks) or at maturation (10 weeks) with syngeneic Trp53 null mammary tissue fragments and monitored for 1 year. Tumors arose sooner from adult hosts (AH) compared to juvenile hosts (JH). However, compared to AH tumors, JH tumors grew several times faster, were more perfused, exhibited a 2-fold higher mitotic index and were more highly positive for insulin-like growth factor receptor phosphorylation. Most tumors in each setting were ER positive (80% JH vs 70% AH) but JH tumors were significantly more ER immunoreactive (p=0.0001) than AH tumors. A differential expression signature (JvA) of juvenile versus adult tumors revealed a luminal transcriptional program. Centroids of the human homologs of JvA genes showed that JH tumors were more like luminal A tumors and AH tumors were more like luminal B tumors. Hierarchical clustering with the JvA human ortholog gene list segregated luminal A and luminal B breast cancers across data sets. These data support the notion that age-associated host physiology greatly influences the intrinsic subtype of breast cancer.

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“…It was shown that pubertal murine mammary glands exposed to sparsely or densely ionizing radiation transiently increased stem cell self-renewal that increased susceptibility to developing ER-negative breast cancer [247]. An exposure of six to eight week old female mouse to a clinically relevant radiation dose (2 Gy of whole body γ-radiation) caused longterm activation of mammary gland genes involved in proliferative and metabolic pathways, which are known to have roles in carcinogenesis [248], and a study which evaluated mammary carcinogenesis initiated by combined exposure to various doses of γ-radiation and chemical carcinogens (1-methyl-1-nitrosourea or 1-methyl-6-phenyl-1H-imidazo [4,5-b]pyridin-2-amine), using a rat model and molecular biological approaches, provided evidence of a multilevel interaction: a synergistic interaction between radiation and a chemical carcinogen at the initiation level and an additive interaction in the incidence of resulting carcinomas [249].…”

Section: Ionizing Radiationmentioning

confidence: 99%

Impact of Environmental Contaminants on Breast Cancer / Wpływ Zanieczyszczenia Środowiska Na Raka Piersi

Kráľová

Jampílek

2015

Ecological Chemistry and Engineering S

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Breast cancer is the most frequent cancer in women. It is believed that among the causes of breast cancer, hereditary factors account for only 5-10% of risk and the environmental exposures to environmental contaminants account for an additional 30-50% of risk. This paper summarizes findings related to the risk of breast cancer due to exposure to following environmental contaminants: polycyclic aromatic hydrocarbons, polychlorinated biphenyls and dioxins, organochlorine pesticides, organophosphorous pesticides, bisphenol A, phthalates, parabens, organic solvents, atmospheric pollutants, alkylphenols, metals, ionizing radiation, electromagnetic field and light pollution. Results obtained in in vitro experiments with breast cancer cell lines and in vivo with model rodents as well as in population based case-control studies are presented and the mode of action of individual environmental contaminants on mammary gland is discussed. Attention is also devoted to the effects of the timing of exposure to environmental contaminants (mainly exposition during development of the mammary gland) on breast cancer risk. Outcomes of professional exposure to some environmental contaminants on breast cancer risk are analysed as well.

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Irradiation of Juvenile, but not Adult, Mammary Gland Increases Stem Cell Self-Renewal and Estrogen Receptor Negative Tumors

Cited by 49 publications

References 50 publications

Densely Ionizing Radiation Acts via the Microenvironment to Promote Aggressive Trp53-Null Mammary Carcinomas

Densely Ionizing Radiation Acts via the Microenvironment to Promote Aggressive Trp53-Null Mammary Carcinomas

Distinct Luminal-Type Mammary Carcinomas Arise from Orthotopic Trp53-Null Mammary Transplantation of Juvenile versus Adult Mice

Impact of Environmental Contaminants on Breast Cancer / Wpływ Zanieczyszczenia Środowiska Na Raka Piersi

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