Epidemiology Research Program: Cancer Research Center of Hawai‘i

Lenora W. M. Loo, PhD
	Assistant Professor (Specialist), Cancer Research Center of Hawai‘i; CRCH Faculty Liaison with Department of Clinical Investigation, Tripler Army Medical Center PhD (Genetics), University of Hawai‘i at Manoa lloo@crch.hawaii.edu

Publication list via PubMed

My research is focused on understanding the molecular mechanisms that both initiate and maintain tumorigenesis. The initiation and maintenance of tumors is often the result of events altering the expression of genes involved in the regulation of cell proliferation, apoptosis, adhesion, and genome stability. Characterizing genomic alterations that affect gene expression, such as loss of heterozygosity (LOH), allelic imbalance, or gene copy number gain and loss, may yield important information for the identification of critical genes and genetic pathways that generate tumors of a specific phenotype and behavior. We use whole genome array-based assays to provide a highly informative assessment of genetic alterations in breast tumors. This approach aims to profile events that may be responsible for the initiation and/or maintenance of breast cancer, and to identify molecular signatures that are characteristic of the different subtypes of breast cancer. The two major histologic subtypes of breast cancer, invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC), differ in their clinical presentation, morphology, and molecular characteristics. IDC is the more commonly occurring histologic subtype, contributing to ~80% of all breast cancers and ILC occurs in 6-10% of breast cancers. It has been demonstrated that the incidence of ILC has been increasing, with no significant increase in the incidence of IDC. Surveillance Epidemiology and End Results data indicate that ILC incidence rates have increased rapidly over the past two decades in the United States, primarily in women over age 50. This differential increase in post-menopausal women has implicated combined (estrogen/progestin) hormone replacement therapy as a risk factor for lobular type breast cancer.As an initial study to identify genomic alterations specific to subtypes of breast cancer, I used high-resolution BAC array comparative genomic hybridization (aCGH) to assay archival breast tumors. In this study we identified several chromosomal regions with genomic alterations (gene copy gain and loss) in a high percentage of breast tumors in 1q (gain) and 16q (loss). We also identified characteristic alterations that were different in frequency and location when the breast tumors were stratified by estrogen receptor (ER) expression status and histologic subtype (ILC or IDC). We observed an association between loss in regions of 4p16, 5q, 8p23, 8p21, 10q25, and 17p11.2 in ER-negative IDC tumors compared with ER-positive IDC tumors. The results from this study demonstrated that subtypes of breast cancers have characteristic profiles, both in their morphology and alteration patterns to their genomes.

We have currently expanded these studies and assayed a larger cohort of ER-positive ILC (77) and IDC (89) archival breast cancer cases with the Affymetrix GeneChip® Mapping 10K SNP Array. The samples in this study were a part of the larger epidemiologic study used to identify the increased incidence in ILC tumors associated with hormone replacement therapy mentioned above. This array is a high resolution whole-genome SNP array (>10,000 individual SNPs) used to identify regions of loss of heterozygosity (LOH). Results from this study have confirmed earlier, preliminary observations, that the breast tumors share common sites of genomic alterations (LOH), regardless of subtype, and have characteristic alterations that occur more commonly in one subtype compared to another. We found SNPs of high frequency LOH (>50%) common to both ILC and IDC tumors predominantly in 11q, 16q, and 17p. By comparing the average frequency of LOH by chromosomal arm, IDC tumors had a higher frequency of LOH on 3p, 5q, 8p, 9p, 20p and 20q than ILC tumors. In addition, a total of 544 individual SNPs throughout the genome demonstrated LOH frequencies that were statistically significant in differentiating IDC and ILC tumors. Based on these results, we are identifying genes of interest (controlling proliferation, adhesion, migration, etc) that have differential LOH frequencies in one subtype compared to the other and assaying for differential protein expression with immuno-histochemistry. The application of this information can be ultimately used to identify characteristic molecular signatures for assessing prognosis and treatment regimens.

Several projects that I am currently involved in include a study to determine if there are differences in genomic alterations in breast cancers from women of different racial backgrounds. African American women are diagnosed at a younger age, present with more aggressive tumors, and experience lower survival rates than Caucasian American women. The samples for the present study were a part of a case-controlled epidemiologic study comparing incidence and prognosis of age and stage matched samples of African American women and Caucasian American women, and were also used to demonstrate that race may be a determinant, or a surrogate for other determinants, of aggressive breast carcinoma and specific cell cycle defects. This study aims to identify underlying molecular events to the genome, with aCGH, which differentiate the clinical behavior of the disease between these two ethnic groups. Another project that I am currently working on is the evaluation of differential genomic alteration profiles of ER-positive breast tumors of women from different ethnic backgrounds. The samples for this study are from a large prospective study called the Multiethnic Cohort Study, involving men and women from different ethnic backgrounds residing in Hawai‘i and Los Angeles.

I am also working with Dr. Loic Le Marchand in the Epidemiology Department at the Cancer Research Center of Hawai‘i, and Graham Casey at USC (Los Angeles, CA). In this study, we compared aCGH results from formalin-fixed paraffin-embedded archival colorectal tumors to fresh-frozen samples from the same tumor as part of a pilot study supported by the Cancer Family Registry. We observed strong concordance for regions of gene copy number gain and loss between the matched FFPE and the fresh-frozen sample for each tumor. Indicating that archival colorectal tumors could be used to reliably identify and characterize genomic alterations in colorectal tumors. In addition, I assayed 20 archived colorectal tumor samples from individuals of different ethnic backgrounds to identify genomic alteration events associated with ethnicity.

It is my intention to continue to conduct high quality research with the goal to elucidate the molecular mechanisms that are fundamental to tumor biology. I am particularly interested in addressing the observed differences in cancer incidence and prognosis associated with race and ethnicity. Hawai‘i is an ideal location to address these questions because of the diverse ethnic groups that reside in the state. I believe that the pursuit to profile tumors and characterize commonalities and differences will lead to a more effective and tailored approach to cancer prevention and treatment.

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Selected Publications

Loo LWM, Ton CC, Wang Y-W, Grove DI, Bouzek HK, Malone KE, Li CI, Hsu, L, Porter PL. (2008) Identification of Genomic Alterations Differentiating Two Major Histologic Subtypes of Breast Cancer. Genes Chromosomes Cancer. 47(12):1049-1066.

Hsu, L, Self, SG, Grove, D, Randolf, T, Delrow, JJ, Loo, LWM, Porter, PL. (2005) Denoising Array-based Comparative Genomic Hybridization Data through the Wavelet Method. Biostatistics. 6(2):211-226.

Loo, LWM, Grove, DI, Neal, CL, Williams, EM, Cousens, LA, Schubert, EL, Holcomb, IN, Massa, H, Glogovac, J, Li, C, Malone, K, Daling, J, Delrow, JJ, Trask, BJ, Hsu, Li, Porter, PL. (2004) Array CGH Analysis of Genomic Alterations in Breast Cancer Sub-Types. Cancer Research 64:8541-8549.

Loo LWM, Secombe J, Little JT, Carlos LS, Yost C, Cheng PF, Flynn EM, Edgar BA, Eisenman RN. (2005) The Transcriptional Repressor, dMnt, is a Regulator of Growth in Drosophila. Mol Cel Biol 25(16):7078-91.

Pierce, SB, Yost, C, Britton, JS, Flynn, EM, Loo, LWM, Edgar, BA, Eisenman, RN. (2004) dMyc is Required for Larval Growth and Endoreplication in Drosophila. Development 131:2317-2327.

Brubaker K, Cowley SM, Huang K, Loo LWM, Yochum GS, Ayer DE, Eisenman RN, Radhakrishnan I. (2000) Solution structure of the interacting domains of the Mad-Sin3 complex: implications for recruitment of a chromatin-modifying complex. Cell. 103(4):655-65.