A mouse model for luminal epithelial like ER positive subtype of human breast cancer.
BACKGROUND
Generation of novel spontaneous ER positive mammary tumor animal model from heterozygous NIH nude mice.


METHODS
Using brother-sister mating with pedigree expansion system, we derived a colony of heterozygous breeding females showing ER-Positive tumors around the age of 6 months. Complete blood picture, differential leukocyte count, and serum levels of Estrogen, Alanine amino transferase (SGPT), Aspartate amino transferase (SGOT), total protein and albumin were estimated. Aspiration biopsies and microbiology were carried out. Gross pathology of the tumors and their metastatic potential were assessed. The tumors were excised and further characterized using histopathology, cytology, electron microscopy (EM), molecular markers and Mouse mammary Tumor Virus - Long Terminal Repeats (MMTV LTR) specific RT-PCR.


RESULTS
The tumors originated from 2nd or 5th or both the mammary glands and were multi-nodulated with variable central necrosis accompanied with an accumulation of inflammatory exudate. Significant increases in estrogen, SGPT, SGOT and neutrophils levels were noticed. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular stroma, adjacent dermis and subcutaneous tissue. Metastatic spread through hematogenous and regional lymph nodes, into liver, lungs, spleen, heart and dermal lymphatics was observed. EM picture revealed no viral particles and MMTV-negativity was confirmed through MMTV LTR-specific RT-PCR. High expression of ER alpha, moderate to high expression of proliferating cell nuclear antigen (PCNA), moderate expression of vimentin and Cytokeratin 19 (K19) and low expression of p53 were observed in tumor sections, when compared with that of the normal mammary gland.


CONCLUSIONS
Since 75% of human breast cancer were classified ER-positive and as our model mimics (in most of the characteristics, such as histopathology, metastasis, high estrogen levels) the ER-positive luminal epithelial-like human breast cancer, this model will be an attractive tool to understand the biology of estrogen-dependant breast cancer in women. To our knowledge, this is the first report of a spontaneous mammary model displaying regional lymph node involvement with both hematogenous and lymphatic spread to liver, lung, heart, spleen and lymph nodes.
Kumar
M J Mahesh
MJ
Centre For Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India. mahesh73@ccmb.res.in
Ponvijay
K S
KS
Nandhini
R
R
Nagarajan
R S
RS
Jose
J
J
Srinivas
G
G
Nagarajan
P
P
Venkatesan
R
R
Kumar
Kishor
K
Singh
S
S
D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D004195:Disease Models, Animal; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006338:Heart Neoplasms / Q000378:metabolism / Q000556:secondary; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D007178:Inbreeding; D053539:Keratin-19 / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D013160:Splenic Neoplasms / Q000378:metabolism / Q000556:secondary; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D004967:Estrogens; D053539:Keratin-19; D018809:Proliferating Cell Nuclear Antigen; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D014746:Vimentin