The morphological, biological and genetic characteristics of low nuclear grade breast carcinoma and their putative precursor lesions

There is evidence to suggest that some special types of breast cancer including tubular and lobular carcinoma and their putative precursor lesions including atypical ductal hyperplasia (ADH), low grade ductal carcinoma in-situ (DOS) and lobular neoplasia (LN) may consist in a family of interrelated lesions. Recently, an attention has been focused on the columnar cell lesion as an early non-obligate precursor lesion of breast cancer. In this study we examined this hypothesis by identifying the morphological and biological characteristics of these lesions. In addition, we used high resolution array comparative genomic hybridization to identify the molecular genetic profiles of invasive lobular and tubular carcinoma and their matched coexisting precursor lesions to investigate their relationship and to provide insight into some of the earliest events leading to invasive breast cancer. Moreover, by validating aspects of our immunohistochemical and in situ hybridization expression data with high throughput tissue microarrays, we identified potential oncogenes and tumour suppressor genes that could potentially drive the progression of BC and have clinicopathological implications on BC. Subsequently, diagnostic, predictive and genetic classifications of breast cancer and their putative precursor lesions were developed. In summary, our results suggest that 1) Tubular and lobular breast carcinoma arise as members of a low nuclear grade breast neoplasia (LNGBN) family, 2) CCLs are early non-obligate precursor components of the LNGBN family, 3) The common cell of origin of the LNGBN family may be the oestrogen receptor-alpha (ER α) positive luminal restricted progenitor cell (ER +/MUC1 + cells) of the terminal duct lobular unit that might acquire stochastic genetic and epigenetic changes that eventually lead to activation of the luminal "A" pathway, 4) Cyclin D1 and MDM4 are oncogenes that potentially lead to activation of the luminal pathway and progression of the LNGBN family, 5) An alteration of E-cadherin (CDH1) appears to be a secondary event resulting in the characteristic morphology of both in situ and invasive lobular lesions, 6) A biological grading system dependent on the balance between Bcl2 protein expression and mitotic figures could accurately reclassify patients with intermediately differentiated, small early stage or ER α negative breast cancers into two groups of low versus high risk of death and recurrence, and 7) The functional status of p53 transcriptional pathways can be assessed using immunohistochemistry protein expression of p53 downstream/regulator genes to accurately discriminate between low and high grade breast carcinoma and to assist routine clinical decision-making