Expression of C-KIT, CD24, CD44s, and COX2 in benign and non-invasive apocrine lesions of the breast

Abstract

Benign apocrine metaplasia (AM) of the adult breast is a very common, but enigmatic lesion. It has been speculated that AM might be a precursor of malignancy or an indicator of a susceptibility of the breast tissue to develop neoplasia, mainly based on comparing the frequency of AM in breast cancer and non-breast cancer patients [1]. Studies using comparative genomic hybridization have supported this by showing similar molecular alterations in benign and malignant apocrine lesions [2]. Few studies, however, have compared expression of biomarkers involved in tumor progression in AM and progressively more advanced atypical apocrine lesions. The expression of C-KIT, COX2, CD24, and CD44s was evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded material of 9 AM, 20 apocrine ductal intraepithelial neoplasia (DIN1c-3) and 40 atypical apocrine lesions (not qualifying for DIN1c-3) and compared to expression of the same biomarkers in adjacent normal ductal epithelium. Of the 66 apocrine lesions, 62 (94 %) did not express C-KIT compared to 4/63 (6 %) of the normal glands (Fisher's exact, p < 0.001). COX2 was expressed in a significantly higher proportion of apocrine lesions than of normal glands (49 vs. 14 %, p < 0.001), and the number of apocrine lesions positive for CD24 was found to be higher with increasing aggressiveness of the lesions (Spearman, p < 0.001). In conclusion, benign and non-invasive proliferative apocrine lesions of the breast display immuno-phenotypical characteristics previously ascribed mainly to malignant transformation. This could lend support to the theory that AM is an early step towards malignant transformation, albeit associated with slow progression to carcinoma.

Loss of c-KIT expression in thyroid cancer cells

“…c-KIT mutations can activate the signal transduction cascades that regulate cell proliferation, apoptosis, chemotaxis and adhesion [25]. In GIST tumors, activating mutations of c-KIT were detected, but also the loss or down-regulation of the c-KIT can be observed linked to neoplastic transformation as for example in breast carcinoma and melanoma [11, 12]. Few and dated studies have analyzed c-KIT expression profiles in thyroid tumors [13–16], finding a correlation with differentiation and growth control of thyroid epithelium and also suggesting a c-KIT loss of function in malignant transformation.…”

“…There are papers showing that c-KIT is highly expressed or mutated in small cell lung cancer [7], leukemia cells [8], colon cancer [9] and neuroblastoma [10]. On the other hand, c-KIT expression is lost in breast cancer [11] and melanoma [12]. Some studies investigated c-KIT expression in thyroid gland and in thyroid malignancies [13–16], suggesting a role for this receptor and its ligand in differentiation and growth control of thyroid epithelium and that this function may be lost following malignant transformation.…”

Triple‐negative apocrine carcinoma: A rare pathologic subtype with a better prognosis than other triple‐negative breast cancers

“…5,8 It is theorized that apocrine differentiation can lead to metaplasia and eventual carcinoma. [7][8][9] The initial definition of apocrine adenocarcinoma varied, but has become more refined over the last several decades. [10][11][12][13] Criteria set forth by Japaze et al defined apocrine carcinoma based on the identification of the following criteria in at least 75% of microscopic fields (a) large cells with abundant eosinophilic cytoplasm, (b) nucleus to cytoplasm of 1:2 or more, (c) nuclei round, large, vesicular nuclei with prominent nucleoli, and (d) sharply defined cell bodies.…”

Identification ofkit-ligand aas the Gene Responsible for the Medaka Pigment Cell Mutantfew melanophore

“…Loss of function of c-Kit in humans gives rise to hypopigmentationdeafness disorders such as piebaldism and is also associated with certain tumor types such as thyroid carcinoma, melanoma, and breast cancer (Ronnstrand 2004;Dahl et al 2015;Zazo Seco et al 2015;Tramm et al 2016;Franceschi et al 2017). Mice with white spotting also harbor heterozygous loss-of-function mutations in the c-Kit gene (Geissler et al 1991).…”