BRCA1 can regulate estrogen receptor-a (ERa) activity. This study tested the hypotheses that Brca1 loss in mammary epithelium alters the estrogenic growth response and that exposure to increased estrogen or ERa collaborates with Brca1 deficiency to accelerate preneoplasia and cancer development. Longer ductal extension was found in mammary glands of Brca1 f/f;MMTV-Cre mice during puberty as compared to wild-type mice. Terminal end bud differentiation was impaired in Brca1 mutant mice with preservation of prolactin-induced alveolar differentiation. Exogenous estrogen stimulated an abnormal sustained increase in mammary epithelial cell proliferation and the appearance of ERa-negative preneoplasia in postpubertal Brca1 mutant mice. Carcinogenesis was investigated using Brca1 f/f;MMTV-Cre mice hemizygous for p53. Exogenous estrogen increased the percentage of mice with multiple hyperplastic alveolar nodules. Targeted conditional ERa overexpression in mammary epithelial cells of mice that were Brca1 mutant and hemizygous for p53 increased the percentage of mice exhibiting multiple hyperplastic nodules, invasive mammary cancers and cancer multiplicity. Significantly more than half of the preneoplasia and cancers were ERa negative even as their initiation was promoted by ERa overexpression.
Real-time technologies can increase the efficiency of obtaining informative biopsies and accelerate interpretation of biopsy pathological review. Cellular aberrations inherent to cancer cells, including nuclear size, can currently be detected, but few technologies are available to evaluate adequacy of specimens in real time. The aims of this study are: 1. to determine if near-infrared reflectance confocal microscopy (RCM) can be used to assess epithelial/stromal content of core needle breast biopsy samples in real time, 2. to determine if epithelial cell nuclear size can be measured on RCM images, and 3. to test if RCM images can be accurately read for presence/absence of histologically relevant features of malignancy. Breast biopsies are obtained following a medically indicated breast core needle diagnostic biopsy for RCM examination. Acetic acid is used as a contrast agent to visualize structures within breast tissue. Structures are identified and optically serially sectioned, and digital images are cataloged. Relative amounts of epithelial, fatty, and collagenous tissue are determined. RCM biopsies are formalin-fixed and stained for hematoxylin and eosin (H and E) comparison with RCM images. RCM data are comparable to data from H and E sections. Epithelial cell nuclear size is measured on stored digital RCM images. We compare RCM and H and E images from 16 patients and 25 core needle biopsy samples.
We have previously shown that increased and deregulated estrogen receptor a expression in the mammary gland leads to the development of proliferative disease and cancer. To address the importance of cyclin D1 in ERa-mediated mammary tumorigenesis, we crossed ERa-overexpressing mice with cyclin D1 knockout mice. Mammary gland morphogenesis was completely interrupted in the ERa-overexpressing cyclin D1-deficient triple transgenic mice. In addition to a highly significant reduction in mammary epithelial cell proliferation, cyclin E was upregulated resulting in DNA damage checkpoint activation and apoptosis. This imbalance between proliferative and apoptotic rates in conjunction with remarkable structural defects and cellular disorganization in the terminal end buds interrupted ductal morphogenesis. Interestingly, the structure of the mammary fat pad was fundamentally altered by the consequences of overexpressing ERa in the epithelial cells in the absence of cyclin D1 illustrating how alterations in the epithelial compartment can impact surrounding stromal composition. Transplantation of embryonic ERa-overexpressing and cyclin D1-deficient mammary epithelium into the cleared fat pad of wild-type mice did not rescue the aberrant mammary gland phenotype indicating that it was intrinsic to the mammary epithelial cells. In conclusion, although cyclin D1 is not essential for proliferation of normal mammary epithelial cells, ERa-overexpressing cells are absolutely dependent on cyclin D1 for proliferation. This differential requirement for cyclin D1 in normal vs abnormal mammary epithelial cells supports the application of cyclin D1 inhibitors as therapeutic interventions in ERa-overexpressing breast cancers.
Rationale: Loss of full length Brca1 in mammary epithelial cells of conditional knockout mice is associated with an abnormal proliferative response that promotes cancer progression following estrogen treatment. This study was conducted to find the mechanisms of this aberrant response. Expression levels of 16 growth factor ligands and receptors at transcriptional level were investigated.
Methods: Post‐pubertal female mice (6–12 months old) were either implanted with a 0.72 mg 60‐day release estrogen or placebo Pellet (n=5, E2/n=5, PLC Brca1Co/CoMMTV‐Cre and n=4, E2 /n=5, PLC WT). Eight weeks after pellet insertion, mice were euthanized, necropsied and mammary glands removed .RNA was extracted, cDNA prepared and RNA expression levels measured by Real Time RT‐PCR.
Results: Steady state RNA expression levels of Tgfβ1, Tgfβ2, TβR‐I, TβR‐II (Two‐Way ANOVA P<0.0001), Tgfβ3 (Two‐Way ANOVA P=0.0115) were lower in the mutant Brca1 mice compared to wild‐type mice. No differences in expression levels of Vegfa, Flt4, Kdr, Figf, Kit, Tgfα, C‐met, Hgf, Fgf7, Fgfr2 gene expression were found.
Conclusions. Loss of full‐length Brca1 in mammary epithelial cells was associated with decreased expression of Tgfβ family members. It is possible that decreased Tgfβ activity contributes to the abnormal and exaggerated growth response seen in Brca1 deficient mammary glands following estrogen treatment.
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