Male Breast Cancer-Immunohistochemical Patterns and Clinical Relevance of FASN, ATF3, and Collagen IV

Abstract

Background: Male breast carcinoma (male BC) is an uncommon neoplasia without individualized strategies for diagnosis and therapeutics. Low overall survival (OS) rates have been reported, mostly associated with patients' advanced stage and older age. Intratumoral heterogeneity versus homogeneity of malignant epithelial cells seems to be an important factor to consider for the development of combination therapies with curative intention.

Objective: In this preliminary study, we aim to provide valuable insight into the distinct clinicopathologic features of male BC.

Material and methods: In a series of 40 male BC patients, we evaluated by immunohistochemistry androgen receptor; activating transcription factor 3 (ATF3); p16; cyclin D1; fatty acid synthase (FASN); fatty acid transport protein 1 (FATP1); β1, β3, β4, and β6 integrins; collagen I and collagen IV; and their interactions. Kaplan-Meier survival curves and log-rank tests were assessed for statistical analysis.

Results: Homogeneous epithelial staining of p16, ATF3, β6 integrin, FASN, and FATP1 was found to be significantly intercorrelated, and associated with high Ki67. These markers also stained tumor stromal fibroblasts. The prognostic analysis showed statistically significant associations of FASN with disease-free survival (DFS) and OS, as well as of ATF3 with OS and collagen IV with DFS.

Conclusions: This study highlights, as a novel finding, the relevance of FASN, ATF3, and collagen IV immunophenotypes, which may have innovative application in the clinical management of male BC.

Keywords: Male breast carcinoma; gynecomastia; immunohistochemistry; molecular markers; prognosis.

Figure 1.

Androgen receptors (A—positive homogeneous epithelial staining 400×, B—positive heterogeneous 400×, C—negative 100×); ATF3 (D—positive homogeneous epithelial staining 400×, E—positive heterogeneous 400×, F—negative 400×); p16 (G—positive homogeneous epithelial staining 400×, H—positive heterogeneous 400×, I—negative 100×); and cyclin D1 (J—positive homogeneous epithelial staining 400×, K—positive heterogeneous 400×, L—negative 100×). ATF3 indicates activating transcription factor 3.

Figure 2.

β1 integrin (A—positive heterogeneous epithelial staining 400×, B—positive stromal staining 400×, C—negative 100×); β3 integrin (D—positive heterogeneous epithelial staining 400×, E—positive stromal staining 400×, F—negative 400×); β4 integrin (G—positive heterogeneous epithelial staining 400×, H—positive stromal staining 400×, I—negative 100×); and β6 integrin (J—positive homogeneous epithelial staining 400×, K—positive heterogeneous epithelial granular staining 100×, L—negative 100×).

Figure 3.

FASN (A—positive homogeneous epithelial staining 400×, B—positive heterogeneous epithelial staining 400×, C—negative 100×); FATP1 (D—positive homogeneous epithelial staining 400×, E—positive heterogeneous epithelial staining 400×, F—negative 400×); collagen I (G—stromal diffuse and intense staining 100×, H—diffuse and intense stromal staining 400×, I—weak/moderate diffuse stromal staining 100×; and collagen IV (J—diffuse and intense stromal staining 100×; K—diffuse and intense stromal staining 400×, L—negative 100×). FASN indicates fatty acid synthase; FATP1, fatty acid transport protein 1.

Figure 4.

Kaplan-Meier survival curves of male BC for FASN, collagen IV, and ATF3: (A)—patients with strong homogeneous FASN membrane cytoplasmatic staining have a significantly shorter DFS (P = .04); (B)—patients with strong homogeneous FASN membrane cytoplasmatic staining have a significantly shorter OS (P = .03); (C)—patients with strong stromal staining for collagen IV have a significantly worse DFS (P = .05); (D)—patients with homogeneous staining for ATF3 have a significantly worse OS (P = .02). ATF3 indicates activating transcription factor 3; BC, breast carcinoma; DFS, disease-free survival; FASN, fatty acid synthase; OS, overall survival.