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Department of Molecular Medicine
 

HuY.jpg Yanfen  Hu,  Ph.D.

Assistant Professor

Profile and Contact Information | Research | Laboratory

RESEARCH

 

Research Program

Breast cancer is the most common malignancy among women in the Western world. Between 5 to 10% of breast cancer cases are hereditary, the majority of which are caused by germline mutations in the breast cancer susceptibility gene BRCA1 or BRCA2. In addition, germline mutations in these two genes also lead to increased risk of hereditary ovarian cancer. The long-term objective of my research is to elucidate the underlying mechanism by which the BRCA genes suppress development of breast and ovarian cancers in women. The ongoing research in my laboratory has been focused on addressing two conundrums regarding BRCA1 functions: 1) Why do mutations in BRCA1 specifically lead to breast and ovarian cancer in women (gender- and tissue-specificity)? 2) Why are somatic mutations of BRCA1 are rarely found in sporadic breast cancers?
A wealth of information regarding BRCA1 functions has been accumulated since cloning of the BRCA1 gene in 1994. BRCA1 has been mainly implicated in two cellular functions: DNA repair and transcriptional regulation. The function of BRCA1 in DNA damage response provides a reasonable molecular explanation for its role as a tumor suppressor. Compromised functions of BRCA1 in DNA repair and checkpoint most likely contribute in a significant manner to cancer susceptibility. However, maintenance of genetic stability alone cannot easily explain why loss of BRCA1 function would increase cancer risks in such a gender and tissue-specific manner, as DNA repair is fundamental and universally important to all cell types in both genders. My earlier work on BRCA1’s potential to remodel chromatin (Hu et al., 1999 Genes & Dev.) and the interaction of BRCA1 with a family of site-specific transcription factors, AP-1/Jun (Hu & Li, 2002 Genes & Dev.), supports a role of BRCA1 in transcriptional regulation. It is conceivable that BRCA1 may modulate tissue-specific gene expression critical to cancer development in breast and ovary.
I. Role of BRCA1 in Estrogen Biosynthesis Based on scientific reasoning and available literature, I proposed several years ago that BRCA1 might down-regulate the estrogen biosynthesis by negatively regulating the expression of aromatase, the rate-limiting enzyme in estrogen biosynthesis. The expression of aromatase and hence the production of estrogen is highly tissue specific. Importantly, estrogen plays a significant role in the development and progression of breast cancer, and aromatase is a clinically proven target for breast cancer treatment. Several pieces of important data from my research support this hypothesis (Hu et al., 2005 Oncogene). To more rigorously test the hypothesis, we have launched additional studies in both tissue culture and animal models in the following three directions:
1. In-depth mechanistic studies at the molecular and cellular levels. Specifically, we will elucidate the mechanism by which BRCA1 is recruited to the tissue-specific promoter of the aromatase gene and the impact of BRCA1 on aromatase promoter activity.
2. Genetic studies in mouse models. We will determine the effect of mouse Brca1 on aromatase expression, circulating estrogen levels, and estrogen-dependent growth in reproductive tissues.
3. Cancer biology studies with clinical samples. We will examine the aromatase expression in ovaries obtained from women carrying wild type or mutant BRCA1/BRCA2 gene.
The potential link between BRCA1 and aromatase expression represents a conceptual advance in understanding the tumor suppressor function of BRCA1. Given that aromatase inhibitors have become one of the most effective drugs in breast cancer treatment, our research will have profound impact on familial breast/ovarian cancer research and prevention.
II. The Potential Role of BARD1 in Hormone Metabolism We are also exploring the potential involvement of BARD1 in aromatase expression. BARD1 is a BRCA1-associated protein and the BRCA1/BARD1 complex displays an E3 ubiquitin ligase activity. It is believed that BRCA1 exists mainly as a heterodimer with BARD1. Interestingly, knockdown of BARD1 has a similar profound effect on aromatase expression (Hu et al., 2005 Oncogene). We are investigating whether BRCA1 and BARD1 regulate aromatase expression as a complex and what role BRCA1/BARD1 E3 ubiquitin ligase might play in this function.

 

Selected Publications

  1. Hu YF, Hao ZL, and Li R: (1999) Chromatin remodeling and activation of chromosomal DNA replication by an acidic transcriptional activation domain from BRCA1. Genes Dev. 13: 637-42.
  2. Miyake T, Hu YF, Yu DS, and Li R: (2000) A functional comparison of BRCA1 C-terminal domains in transcription activation and chromatin remodeling. J Biol Chem. 275: 40169-73.
  3. Hu YF, Miyake T, Ye Q, and Li R: (2000) Characterization of a novel trans-activation domain of BRCA1 that functions in concert with the BRCA1 C-terminal (BRCT) domain. J Biol Chem. 275: 40910-5.
  4. Ye Q, Hu YF, Zhong H, Nye AC, Belmont AS, and Li R: (2001) BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. J Cell Biol. 155: 911-21.
  5. Hu YF and Li R: (2002) JunB potentiates function of BRCA1 activation domain 1 (AD1) through a coiled-coil-mediated interaction. Genes Dev. 16: 1509-17.
  6. Wu Y, Ghosh S, Nishi Y, Yanase T, Nawata H, and Hu Y: (2005) The orphan nuclear receptors NURR1 and NGFI-B modulate aromatase gene expression in ovarian granulosa cells: a possible mechanism for repression of aromatase expression upon luteinizing hormone surge. Endocrinology 146: 237-46.
  7. Ghosh S, Wu Y, Li R, and Hu Y: (2005) Jun proteins modulate the ovary-specific promoter of aromatase gene in ovarian granulosa cells via a cAMP-responsive element. Oncogene 24: 2236-46.
  8. Hu Y*, Ghosh S, Amleh A, Yue W, Lu Y, Katz A, and Li R*: (2005) Modulation of aromatase expression by BRCA1: a possible link to tissue-specific tumor suppression. Oncogene 24: 8343-8. (*co-corresponding authors).
  9. Wu Y, Lu Y, Hu Y, and Li R: (2005) Cyclic AMP-dependent modulation of gonad-selective TAF(II)105 in a human ovarian granulosa cell line. J Cell Biochem. 96: 751-9.
  10. Ghosh S, Lu Y, Katz A, Hu Y, and Li R: (2007) Tumor suppressor BRCA1 inhibits a breast cancer-associated promoter of the aromatase gene (CYP19) in human adipose stromal cells. Am J Physiol Endocrinol Metab. 292: E246-52.
  11. Lu Y, Amleh A, Sun J, Jin X, McCullough SD, Baer R, Ren D, Li R, and Hu Y: (2007) Ubiquitination and proteasome-mediated degradation of BRCA1 and BARD1 during steroidogenesis in human ovarian granulosa cells. Mol Endocrinol. 21: 651-63.
  12. Ghosh S, Lu Y, and Hu Y: (2008) A Role of CREB in BRCA1 Constitutive Promoter Activity and Aromatase Basal Expression. Intl J Biomedical Sci. 4(4): 260-5.
  13. Hu Y: (2009) BRCA1, hormone, and tissue-specific tumor suppression. (Review) Int. J. Biol. Sci. 5(1): 20-7.
  14. Ghosh S, Choudary A, Ghosh S, Musi N, Hu Y, and Li R: (2009) IKK{beta} mediates cell shape-induced aromatase expression and estrogen biosynthesis in adipose stromal cells.Mol Endocrinol. 23: 662-70.
  15. Wang H, Li R, and Hu Y: (2009) The alternative noncoding exons 1 of aromatase (cyp19)gene modulate gene expression in a posttranscriptional manner.Endocrinology 150: 3301-7. [Epub ahead of print].

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