Breast cancer is among one of the most common cancers that occur in women in the United States; it accounts for one in four female cancers, making it one of the most important cancers in the Western world. Breast cancer results from the abnormal growth of the mammary gland, which is normally modulated by estrogen, the female hormone produced by the ovaries. The activity of estrogen is mediated by the estrogen receptor (ER) which in turn regulates the expression of genes necessary for the growth and development of the mammary gland. The presence and absence of the ER serves as a key prognostic marker in breast cancer development. The majority of breast cancers initially develop as hormone dependent, which implies that the presence of estrogen can enhance the progression of the cancer. Hormone dependent breast cancers are typically treated with hormone ablation therapy and/or antiestrogen treatment. However, hormone responsive breast cancer frequently develops into a more aggressive phenotype that is hormone independent. In many cases, the ER is still present, but its role in hormone refractory breast tumorigenesis is unclear. A potential mechanism may involve endocrine disruptors including heavy metals such as cadmium. Studies have suggested that cadmium may enhance the ER function and promote the development of breast cancer. Cadmium is as an environmental contaminant that enters the body through diet or cigarette smoke. Recent studies have suggested that cadmium can stimulate estrogen receptor (ER) activity and may promote neoplastic growth in mice. (Stoica et al. 2000, Martin et al., 2003). This suggests that increased incidences of breast cancer in the US may be associated with human exposure to cadmium. My lab's preliminary findings also suggest that cadmium can enhance breast cancer cell growth in a hormone independent manner and promote both classical ER target genes (i.e. cycD1, c-myc and CTD) and non classical ER target genes (""""""""non-ER"""""""") target genes (i.e. cyclin E1, cdk2 and ACTR). This suggests that in addition to the classical ER pathway, cadmium may activate an alternate signaling mechanism. How cadmium regulates these """"""""non-ER"""""""" target genes and the role of ER in this alternate pathway are unclear. The work proposed here is aimed at characterizing the role of cadmium in breast cancer cell proliferation and map out the molecular mechanism of cadmium's role in regulating the expression of both ER and """"""""non ER"""""""" target gene expression. The objectives of this study are to characterize the role of cadmium in breast carcinogenesis and dissect the molecular mechanism of its action. Results from this study will not only provide a better understanding of how environmental contaminants such as cadmium can promote breast cancer, but also offer new insights to how the estrogen receptor can regulate both classical and non-classical ER target gene expression. Additionally, the results obtained from this research will have significant clinical contributions, including screening for heavy metal toxicities, identifying heavy metal-associated breast cancer cases, designing more effective therapeutics for hormone- refractory breast cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
3R15CA121983-01A1S1
Application #
7659086
Study Section
Special Emphasis Panel (ZRG1-F09-W (20))
Program Officer
Ogunbiyi, Peter
Project Start
2007-08-21
Project End
2010-07-31
Budget Start
2008-03-01
Budget End
2010-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$53,106
Indirect Cost
Name
Dominican University
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
074664855
City
San Rafael
State
CA
Country
United States
Zip Code
94901
Ponce, Esmeralda; Louie, Maggie C; Sevigny, Mary B (2015) Acute and chronic cadmium exposure promotes E-cadherin degradation in MCF7 breast cancer cells. Mol Carcinog 54:1014-25
Ponce, Esmeralda; Aquino, Natalie B; Louie, Maggie C (2013) Chronic cadmium exposure stimulates SDF-1 expression in an ER? dependent manner. PLoS One 8:e72639
Lubovac-Pilav, Zelmina; Borràs, Daniel M; Ponce, Esmeralda et al. (2013) Using expression profiling to understand the effects of chronic cadmium exposure on MCF-7 breast cancer cells. PLoS One 8:e84646
Aquino, Natalie B; Sevigny, Mary B; Sabangan, Jackielyn et al. (2012) The role of cadmium and nickel in estrogen receptor signaling and breast cancer: metalloestrogens or not? J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 30:189-224
Siewit, Christina L; Gengler, Bridget; Vegas, Esera et al. (2010) Cadmium promotes breast cancer cell proliferation by potentiating the interaction between ERalpha and c-Jun. Mol Endocrinol 24:981-92