Existing biomarkers and cancer prevention strategies are limited as the biology of breast tumor initiation remains poorly understood.
We aim to elucidate mammary epithelial cells that participate in tumorigenesis as a means of developing markers for risk stratification and targets for prevention. Important clues to the identity of these cells come from epidemiologic and our preliminary data. Early full-term pregnancy is one of the most effective protections against breast cancer in most women but not in BRCA1/2 mutation carriers. We investigated parity-associated variation in gene expression profiles of distinct cell types in normal breast tissues of nulliparous and parous women. The most significant differences were seen in CD44+ cells where many genes important in self-renewal and differentiation (e.g., p27, TGFB) were lower in parous women than in nulliparous and in parous BRCA1/2 mutation carriers. The numbers of p27+ and Ki67+ cells were also significantly lower in parous than in nulliparous women except in parous BRCA1/2 cases. The majority of p27+ cells were also estrogen receptor positive. In explant cultures of breast tissues, inhibition of TGFB increased proliferation with a concomitant decrease of p27+ cells implying that p27 due to TGFB is key for keeping breast epithelial progenitors in a quiescent state. Based on these preliminary data, we hypothesize that (1) a subset of p27+ and Ki67+ cells represent quiescent and proliferating hormone-responsive breast epithelial progenitors, respectively, (2) p27 and TGFJ3 play an important role in keeping these progenitors quiescent, (3) the number of these progenitors correlates with breast cancer risk, and (4) mechanisms regulating p27+ progenitors are perturbed in BRCA1/2 mutation carriers and this contributes to their high risk. To test these hypotheses we propose: 1. To characterize the molecular profiles of p27+ and Ki67+ human breast epithelial cells from normal breast tissue of women with different risk of breast cancer. 2. To investigate the role of p27 and signaling pathways that regulates its expression in human breast epithelial cell proliferation and differentiation. 3. To characterize the role of p27 in regulating the abundance of mammary epithelial progenitors and its effect of this on mammary tumorigenesis in animal models.
The relationship between the number and characteristics of breast epithelial progenitors and breast cancer risk is an important but poorly studied area of research. The proposed project will investigate candidate regulators of human breast epithelial progenitors and their relevance for breast cancer risk, which may open new venues for improved risk prediction and chemoprevention.
|Hinohara, Kunihiko; Wu, Hua-Jun; Vigneau, Sébastien et al. (2018) KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance. Cancer Cell 34:939-953.e9|
|Wan, Lixin; Xu, Kexin; Wei, Yongkun et al. (2018) Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function. Mol Cell 69:279-291.e5|
|Xiao, Tengfei; Li, Wei; Wang, Xiaoqing et al. (2018) Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy. Proc Natl Acad Sci U S A 115:7869-7878|
|Zhang, Jinfang; Bu, Xia; Wang, Haizhen et al. (2018) Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553:91-95|
|Li, Andrew G; Murphy, Elizabeth C; Culhane, Aedin C et al. (2018) BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1? activation. Proc Natl Acad Sci U S A 115:E9600-E9609|
|Wu, Yanming; Zhang, Zhao; Cenciarini, Mauro E et al. (2018) Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2-ER?-GREB1 Transcriptional Axis. Cancer Res 78:671-684|
|Witwicki, Robert M; Ekram, Muhammad B; Qiu, Xintao et al. (2018) TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer. Cell Rep 25:1255-1267.e5|
|Jeselsohn, Rinath; Bergholz, Johann S; Pun, Matthew et al. (2018) Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations. Cancer Cell 33:173-186.e5|
|Dreijerink, Koen M A; Timmers, H T Marc; Brown, Myles (2017) Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1. Endocr Relat Cancer 24:T135-T145|
|Rashidian, Mohammad; Ingram, Jessica R; Dougan, Michael et al. (2017) Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells. J Exp Med 214:2243-2255|
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