""""""""Premalignant"""""""" breast lesions are both risk factors and precursors of invasive breast cancer [IBC]. The evolutionary stages of these lesions include typical hyperplasia [TH], atypical hyperplasia [AH], and carcinoma in situ [CIS]. Clinically, it would be very important to identify biomarkers able to distinguish lesions likely to progress from those which will not, in order to take appropriate preventive measures. Furthermore, a knowledge of the molecular correlates of these stages might provide targets for focusing these preventive measures. We have therefore assembled a large evolutionary tumor bank of archival breast tissues representing these stages. Using immunohistochemistry [IHC], we have shown that lesions of all stages proliferate faster than normal breast epithelium, independent of hormonal control, and also have altered rates of apoptosis. We are able to distinguish three grades of CIS based on five IHC markers (ER and PgR, p53, c-erbB-2, and Ki67) as well as on histomorphology. We have also developed microdissection techniques suitable for isolating DNA from these archival specimens for allelic imbalance (loss-of- heterozygosity) studies, and RNA for differential display studies, from relatively pure lesions. These techniques have already allowed us to sow that there is a clonal progression from one stage to the next in lesions of different stages in the same breast. Finally, as spin-offs of this project, we have found evidence of a gene required for metastasis near a tumor suppressor gene on chromosome 14q, forming the basis for the new Project 4, and have discovered in several TH lesions the same super-active estrogen receptor polymorphism, which may therefore be important in the development of premalignant breast disease. To pursue the goals of identifying markers of risk and evolutionary progression in premalignant breast lesions, we now propose: (1) To identify growth regulatory factors, including receptors along with proliferation and apoptosis markers, which are associated with the development and progression of human premalignant breast disease and which are clinically associated with risk of developing invasive breast cancer [IBC]; (2) to identify invasion-related factors, including certain adhesion molecules and the urokinase-type plasminogen activator system, which are associated specifically with progression of CIS to IBC; and (3) To identify, by differential display and appropriate RT-PCR and immunohistochemical confirmation, new gene products whose loss or gain is associated with progression of premalignant lesions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA030195-20
Application #
6334931
Study Section
Project Start
2000-08-01
Project End
2001-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
20
Fiscal Year
2000
Total Cost
$181,487
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Park, Jun Hyoung; Vithayathil, Sajna; Kumar, Santosh et al. (2016) Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer. Cell Rep 14:2154-2165
Pathiraja, Thushangi N; Nayak, Shweta R; Xi, Yuanxin et al. (2014) Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer. Sci Transl Med 6:229ra41
Zhang, Yi; Tseng, Chun-Chih; Tsai, Yuan-Li et al. (2013) Cancer cells resistant to therapy promote cell surface relocalization of GRP78 which complexes with PI3K and enhances PI(3,4,5)P3 production. PLoS One 8:e80071
Machado, Heather L; Kittrell, Frances S; Edwards, David et al. (2013) Separation by cell size enriches for mammary stem cell repopulation activity. Stem Cells Transl Med 2:199-203
Zhang, Xiaomei; Claerhout, Sofie; Prat, Aleix et al. (2013) A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res 73:4885-97
Boone, David N; Lee, Adrian V (2012) Targeting the insulin-like growth factor receptor: developing biomarkers from gene expression profiling. Crit Rev Oncog 17:161-73
Casa, Angelo J; Potter, Adam S; Malik, Simeen et al. (2012) Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth. Breast Cancer Res Treat 132:61-73
Creighton, Chad J (2012) Molecular classification and drug response prediction in cancer. Curr Drug Targets 13:1488-94
Pathiraja, Thushangi N; Shetty, Priya B; Jelinek, Jaroslav et al. (2011) Progesterone receptor isoform-specific promoter methylation: association of PRA promoter methylation with worse outcome in breast cancer patients. Clin Cancer Res 17:4177-86
Heckman-Stoddard, B M; Vargo-Gogola, T; Herrick, M P et al. (2011) P190A RhoGAP is required for mammary gland development. Dev Biol 360:1-10

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