SUN-288 - Creating New Models for Male Breast Cancer: Hormone-Dependent Tumorigenesis using the August Copenhagen Irish Rat

Background: Male breast cancer (MBC) is rare yet clinically significant, representing ~1% of all breast cancers and < 1% of male cancers. Most MBC tumors are hormone receptor-positive, highlighting the central role of sex steroid signaling. However, because men have been largely excluded from clinical trials, MBC treatment is still modeled on female breast cancer (FBC), despite biological differences that contribute to poorer outcomes, higher toxicity, and frequent discontinuation of endocrine therapies. MBC also lacks dedicated screening strategies and, critically, lacks biological samples and disease-specific in vitro models. To address this gap, we are developing an integrated in vivo/in vitro platform using the hormone-responsive August Copenhagen Irish (ACI) rat to define how estrogen and progesterone drive male mammary tumorigenesis.

Methods: We performed a controlled hormone supplementation study in 32 male ACI rats (n=8 per group: E2 alone, MPA alone, sham pellets, or E2+MPA) and three female ACI rats (E2 alone) as positive controls. Males received either slow-release pellets containing 27 mg 17β-estradiol (E2), 20-30mg medroxyprogesterone acetate (MPA), sham (empty) pellets, or a combination of E2 and MPA, with pellet replacement at 4 months. Mammary glands were palpated weekly. Endpoints were based on tumor burden or health status. At necropsy, mammary tissues were assessed grossly and histologically, and palpable tumors were distinguished from hyperplastic lesions.

Results: Preliminary data show that ACI males developed mammary tumors only with combined E2+MPA treatment, with 50% of the group forming tumors by month 8, indicating that progesterone is required for tumor initiation in males. Rats receiving E2 alone exhibited marked hyperplasia and visible lactation but did not form tumors, underscoring the cooperative hormone effect. Rats receiving MPA alone or sham pellets did not form hyperplasia or tumors. All three female positive controls developed tumors by month 5. We also established stable organoid cultures and epithelial monolayers from ACI tumors and hyperplastic glands, which expand reliably across passages and withstand freeze–thaw cycles. Immunohistochemical and immunofluorescence analyses of tissues and cell monolayers confirmed tumor expression of estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR), consistent with the receptor profile of human MBC.

Conclusions: These organoids and monolayers represent the first in vitro models of male breast cancer and, together with our in vivo system, provide a foundational platform for dissecting hormone-driven MBC biology. This work addresses a major gap in the field and sets the stage for future mechanistic and translational studies aimed at improving MBC-specific therapies.

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