Shaojin You

Publications (5)18.76 Total impact

• Article: Circadian clock coordinates cancer cell cycle progression, thymidylate synthase, and 5-fluorouracil therapeutic index.

  Patricia A Wood, Jovelyn Du-Quiton, Shaojin You, William J M Hrushesky
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  ABSTRACT: Dysregulated cellular proliferation is a characteristic property of cancer. We show that, despite this fact, cancers maintain high amplitude, circadian rhythms in their growth, DNA synthesis, and mitosis. These patterns are accompanied by the daily traverse of BMAL-1 protein between the cytoplasm, where it is produced, and nucleus, where it influences timing of cancer cell proliferation. This core clock gene product gates cancer cell proliferation by coordinating clock-controlled proteins, thymidylate synthase [thymidylate synthase activity (TSA) cell DNA replication], WEE-1 (cell mitosis), and vascular endothelial growth factor (growth). 5-Fluorouracil (5-FU)-induced host bone marrow and gut toxicity and tumor shrinkage following administration at six equispaced times of day allowed determination of circadian relationships among tumor growth, relevant clock, and clock-controlled proteins and dependence of 5-FU target availability (TSA) in normal and cancer tissues and resultant 5-FU toxic-therapeutic index. The time of day (hours after lights on) of low TSA in each tissue and tumor is respectively associated with greatest toxicity to that tissue and greatest tumor shrinkage. 5-FU treatment near daily awakening results in least damage to bone marrow and gut, greatest antitumor effect, and best survival. This time of day is associated with maximum tumor nuclear BMAL-1 and total cell WEE-1 protein. The described chain of events, for the first time, links cancer cell clock proteins, cancer cell DNA synthesis, proliferation, TSA, and 5-FU toxic-therapeutic index, explaining the dependence of cancer outcome on circadian timing of 5-FU.
  Molecular Cancer Therapeutics 09/2006; 5(8):2023-33. · 5.23 Impact Factor
• Article: Developmental abnormalities in multiple proliferative tissues of Apc(Min/+) mice.

  Shaojin You, Masami Ohmori, Maria Marjorette O Peña, Basel Nassri, Jovelyn Quiton, Ziad A Al-Assad, Lucy Liu, Patricia A Wood, Sondra H Berger, Zhijian Liu, Michael D Wyatt, Robert L Price, Franklin G Berger, William J M Hrushesky
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  ABSTRACT: Germ-line mutation of the Apc gene has been linked to familial adenomatous polyposis (FAP) that predisposes to colon cancer. Apc(Min/+) mice, heterozygous for the Apc gene mutation, progressively develop small intestinal tumours in a manner that is analogous to that observed in the colon of patients with FAP (Su et al. 1992; Fodde et al. 1994; Moser et al. 1995). We have studied the effects of Apc gene mutation on murine intestinal and extra-intestinal, proliferatively active tissues. We have contrasted the histology to that of the age- and sex-matched wild-type C57BL/6 mice. Histological assessment of the normal appearing intestinal mucosa demonstrates minimal change in size of crypts. In contrast, villi are longer in the ileum of Apc(Min/+) mice relative to C57BL/6 mice at 12 and 15 weeks of age. Vigorous splenic haematopoiesis in Apc(Min/+) mice was seen at 12 and 15 weeks of age, as reflected by marked splenomegaly, increased splenic haematopoietic cells and megakaryocytes. Peripheral blood counts, however, did not differ between C57BL/6 and Apc(Min/+) mice at 15 weeks of age. Lymphoid depletion in Apc(Min/+) mice was characterized by diminished numbers of splenic lymphoid follicles and small intestinal Peyer's patches. The ovaries of 12- and 15-week-old Apc(Min/+) mice exhibited increased numbers of atretic follicles, and estrous cycling by serial vaginal smears showed tendency of elongation in the mutant mice during these age ranges. The testicles of 10-week-old Apc(Min/+) mice showed increased numbers of underdeveloped seminiferous tubules. Collectively, these data suggest that, in addition to its obvious effects upon intestinal adenoma formation, Apc gene mutation causes impairment of developmental and apparent differentiation blockade in proliferative tissues, including those of the haematopoietic system, lymphoid and reproductive tract.
  International Journal of Experimental Pathology 07/2006; 87(3):227-36. · 2.57 Impact Factor
• Article: Cancer growth and spread are saltatory and phase-locked to the reproductive cycle through mediators of angiogenesis.

  Patricia A Wood, Kathleen Bove, Shaojin You, Ann Chambers, William J M Hrushesky
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  ABSTRACT: The frequency of breast cancer metastatic spread is affected by the menstrual cycle phase of its resection. Breast cancer growth, post-resection spread, and cure frequency are each modulated by the estrous cycle in C(3)HeB/FeJ mice. Tumor metastases are 2- to 3-fold more frequent when the resection is done during diestrus as compared with estrus. Tumor angiogenesis is essential for both cancer growth and lethal metastatic cancer spread. The balance between vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) modulates new blood vessel formation and blood vessel permeability. Sex hormones modulate the expression of these key angiogenesis regulators in the endometrium and uterus. We, therefore, asked whether the estrous cycle modulates the density of CD31-positive vessels within the tumor, the permeability of tumor blood vessels, levels of VEGF and bFGF immunoreactive protein in normal breast and breast cancer, and whether expression of these genes are modulated by the estrous cycle stage in C(3)HeB/FeJ mice. We find that tumor blood vessel density and blood volume do not vary throughout the cycle; however, tumor capillary permeability is regulated by the estrous cycle being highest in diestrus, the cycle stage associated with the highest cancer growth rate and the highest frequency of post-resection cancer metastasis. VEGF protein levels in breast cancer are >100-fold higher than in normal breast. VEGF protein in this mammary tumor varies with the estrus cycle with highest levels in proestrus. In a non-breast tumor, methylcholantrenene A sarcoma, from CD(2)F(1) mice, tumor VEGF protein also varies with the estrus cycle with highest levels in proestrus and diestrus. VEGF gene expression in the mammary tumor does not change significantly across the cycle, but is modulated by the cycle in normal breast tissue. bFGF protein concentration is 6-fold higher in normal breast than in breast cancer. bFGF protein pattern in both tumor and breast are similar, opposite to VEGF, and affected by oophorectomy. bFGF message is modulated by the cycle in both breast cancer and normal breast. The changes in breast cancer capillary permeability, VEGF, and bFGF that occur during each fertility cycle, in breast tissue and breast cancer, putatively in response to cyclical changes in sex hormones, might contribute, at least in part, to both the modulation of cancer growth and post-resection breast cancer spread by the fertility cycle. These fertility cycle-induced effects on tumor biology also seem to extend to non-breast cancer biology.
  Molecular Cancer Therapeutics 07/2005; 4(7):1065-75. · 5.23 Impact Factor
• Article: Daily coordination of cancer growth and circadian clock gene expression.

  Shaojin You, Patricia A Wood, Yin Xiong, Minoru Kobayashi, Jovelyn Du-Quiton, William J M Hrushesky
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  ABSTRACT: Circadian coordination in mammals is accomplished, in part, by coordinate, rhythmic expression of a series of circadian clock genes in the central clock within the suprachiasmatic nuclei (SCN) of the hypothalamus. These same genes are also rhythmically expressed each day within each peripheral tissue. We measured tumor size, tumor cell cyclin E protein, tumor cell mitotic index, and circadian clock gene expression in liver and tumor cells at six equispaced times of day in individual mice of a 12-h light, 12-h dark schedule. We demonstrate that C3HFeJ/HeB mice with transplanted syngeneic mammary tumor maintain largely normal circadian sleep/activity patterns, and that the rate of tumor growth is highly rhythmic during each day. Two daily 2.5-fold peaks in cancer cell cyclin E protein, a marker of DNA synthesis, are followed by two daily up-to-3-fold peaks in cancer cell mitosis (one minor, and one major peak). These peaks are, in turn, followed by two prominent daily peaks in tumor growth rate occurring during mid-sleep and the second, during mid-activity. These data indicate that all therapeutic targets relevant to tumor growth and tumor cell proliferation are ordered in tumor cells within each day. The daily expression patterns of the circadian clock genes Bmal1, mPer1, and mPer2, remain normally circadian coordinated in the livers of these tumor bearing mice. Bmal1 gene expression remains circadian rhythmic in cancer cells, although damped in amplitude, with a similar circadian pattern to that in normal hepatocytes. However, tumor cell mPer1 and mPer2 gene expression patterns fail to maintain statistically significant daily rhythms. We conclude that, if core circadian clock gene expression is essential to gate tumor cell proliferation within each day, then there may be substantial redundancy in this timing system. Alternatively, the daily ordering of tumor cell clock gene expression may not be essential to the daily gating of cancer cell DNA synthesis, mitosis and growth. This would indicate that host central SCN-mediated neuro-humoro-behavioral controls and/or daily light-induced changes in melatonin or peripherally-induced rhythms such as those resulting from feeding, may be adequate for the daily coordination of cancer cell expression of proliferation related therapeutic targets.
  Breast Cancer Research and Treatment 06/2005; 91(1):47-60. · 4.43 Impact Factor
• Article: Creation of a stable mammary tumor cell line that maintains fertility-cycle tumor biology of the parent tumor.

  Shaojin You, Wei Li, Minoru Kobayashi, Yin Xiong, William Hrushesky, Patricia Wood
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  ABSTRACT: A mammary tumor cell line, designated MTCL, was successfully established from a mouse primary mammary tumor (MTP). The MTCL cells retain cytokeratin and both estrogen receptor (ER) and progesterone receptor (PR) in vitro. In vitro exposure of MTCL cells to progesterone causes a decrease in the cellular (3)H-thymidine uptake, indicating an inhibition by progesterone on MTCL cellular deoxyribonucleic acid synthesis, whereas exposure of the cells to a high dose of estrogen (15 pg/ml) for 48 h causes an increase of (3)H-thymidine uptake. We inoculated both MTP or MTCL tumor cells into normal cycling female C(3)HeB/FeJ mice and demonstrated that the post-resection metastatic recurrence of MTCL tumors, like the original MTP tumors, depends on the time of tumor resection within the mouse estrous-cycle stage. Both MTCL and MTP tumors have similar histological appearances with the exception of less extensive tumor necrosis and higher vascularity in MTCL tumors. Equivalent levels of sex hormone receptors (ER alpha, ER beta, and PR), epithelial growth hormone receptors (Her2/neu, EGFR1), tumor suppressors (BRCA1, P53), and cell apoptosis-relevant protein (bcl-xl) were found in these in vivo tumors by immunohistochemistry. Cyclin E protein, however, was significantly higher in MTP tumors compared with MTCL tumors. Our results indicate that MTCL cells retain many of the biologic features of the original MTP primary tumor cells, and to our knowledge, it is the first in vitro cell line that has been shown to maintain the estrous-cycle dependence of in vivo cancer metastasis.
  In Vitro Cellular & Developmental Biology - Animal 06/2004; 40(7):187-95. · 1.31 Impact Factor