Cell clusters overlying focally disrupted mammary myoepithelial cell layers and adjacent cells within the same duct display different immunohistochemical and genetic features: implications for tumor progression and invasion

Abstract

The epithelial component of normal and noninvasive breast tumor tissue is physically separated from the stroma by both the myoepithelial cells and the basement membrane (BM). Myoepithelial cells are joined by intermediate or gap junctions and a number of intercellular adhesion molecules, forming a continuous sheet or belt that encircles the epithelial cells (except at the terminal ductal-lobular unit, within which about 20% of the epithelial cells are reported to be in direct contact with the BM) BM = basement membrane; DCIS = ductal carcinoma in situ; ER = estrogen receptor; H & E = hematoxylin and eosin; LOH = loss of heterozygosity; MI = microsatellite instability; PCR = polymerase chain reaction; SMA = smooth muscle actin. AbstractIntroduction Our previous studies detected focal disruptions in myoepithelial cell layers of several ducts with carcinoma in situ. The cell cluster overlying each of the myoepithelial disruptions showed a marked reduction in or a total loss of immunoreactivity for the estrogen receptor (ER). This is in contrast to the adjacent cells within the same duct, which were strongly immunoreactive for the ER. The current study attempts to confirm and expand previous observations on a larger scale.

Myoepithelial Cell Differentiation Markers in Ductal Carcinoma in Situ Progression

“…14e16 Further studies report that tumor cells adjacent to focally disrupted myoepithelium can display distinct phenotypes, including estrogen receptor negativity, genetic instabilities, increased expression of invasion-related genes, and aberrant E-cadherin expression. 17,18 Overall, these data support an active role for the myoepithelium in suppressing DCIS progression and implicate loss of this function as critical for the transition to invasive disease.…”

Consensus regarding the diagnosis, prognosis and treatment of canine mammary tumors: benign mixed tumors, carcinomas in mixed tumors and carcinosarcomas

“…The essential condition for stromal invasion is the rupture of the basement membrane and the myoepithelial cell layer (41). In human medicine, the evaluation of the integrity of the myoepithelial/basal cell layer is often an important tool in the differential diagnosis between in situ and invasive malignant lesions (61,67).…”

“…Bertagnolli et al (2009) (3) observed a decrease in p63 expression in female dog CMTs, suggesting a loss of myoepithelial cells in these areas and supporting the invasive and progressive character of these tumors. However, the mechanisms that culminate in the descontinuity of this layer are poorly understood (41). Studies of mammary neoplasms of the 91 human breast show a decrease in the expression of oestrogen receptors via epithelial cells and tumor suppressor proteins (e.g., maspin, WT-1, and p73) near areas with the loss of myoepithelial cells, which contributes to tumor aggressiveness and invasiveness (41,42,65).…”

“…However, the mechanisms that culminate in the descontinuity of this layer are poorly understood (41). Studies of mammary neoplasms of the 91 human breast show a decrease in the expression of oestrogen receptors via epithelial cells and tumor suppressor proteins (e.g., maspin, WT-1, and p73) near areas with the loss of myoepithelial cells, which contributes to tumor aggressiveness and invasiveness (41,42,65).…”

Microenvironmental regulation of cancer development

“…Focal breakdown of myoepithelial cell layer and BM at sites of white blood cell infiltration have also been observed in DCIS [66]. Emphasizing the necessity of changes in both in "seed" and "soil" for progression, epithelial cell clusters overlying the disrupted myoepithelial layers were different from adjacent cells within the same duct with respect of ER (estrogen receptor) status, frequency or pattern of LOH and/or MSI, and expression of tumor progression related genes, normal stem cell and proliferation markers, and showed invasion into the stroma and blood vessels-like structures [67][68][69]. Since tumor-stromal interactions are bi-directional, identification of the initiating events requires further study.…”