Abstract
Basal breast cancer comprises ~15% of invasive ductal breast cancers, and presents as high-grade lesions with aggressive clinical behavior. Basal breast carcinomas express p63 and cytokeratin 5 (CK5) antigens characteristic of the myoepithelial lineage, and typically lack Her2/neu and hormone receptor expression. However, there is limited data about the precursor lesions from which they emerge. Here we wished to determine whether comedo-ductal carcinoma in situ (comedo- DCIS), a high-risk in situ breast lesion, serve as precursors for basal-like breast cancer. To determine this link, p63, CK5, Her2/neu, epidermal growth factor receptor (EGFR), estrogen receptor (ER) and progesterone receptor (PgR) expression were analyzed by immunohistochemistry in 17 clinical comedo- and 12 noncomedo-DCIS cases, and in tumors derived from unfractionated and CK5-overexpressing subpopulation (MCF10DCIS.com-CK5(high)) of MCF10DCIS.com cells, a model representative of clinical comedo-DCIS. p63 and Her2/neu coexpression was analyzed by immunofluorescence double labeling. A novel p63/CK5/Her2/neu expressing subpopulation of cells that are ER-/PgR-/EGFR- were identified in the myoepithelial and luminal areas of clinical comedo-DCIS and tumors derived from unfractionated MCF10DCIS.com and MCF10DCIS.com-CK5(high) cells. These data suggest that p63 and Her2/neu expressors may share a common precursor intermediate. P63, but not Her2/neu, expression was significantly associated (P = 0.038) with microinvasion/recurrence of clinical comedo-DCIS, and simultaneous expression of p63 and Her2/neu was marginally associated (P = 0.067) with comedo-DCIS. These data suggest that p63/Her2/neu expressing precursor intermediate in comedo-DCIS may provide a cellular basis for emergence of p63+/Her2/neu- or p63+/Her2/neu+ basal-like breast cancer, and that p63/Her2/neu coexpression may serve as biomarkers for identification of this subgroup of basal-like breast cancers.
Highlights
Clinical breast cancer consists of a heterogeneous group of tumors that are only partially distinguishable by morphological presentation
P63 and cytokeratin 5 (CK5) expressions are maintained in infiltrating invasive cancer cells whereas Her2/neu expression is reduced in invasive and basally located cancer cells (Fig. 1, arrows in Her2 staining in Days 47 and 53 lesions)
We have identified for the first time a novel p63/Her2/neu coexpressing subgroup that provides a precursor link between comedo-ductal carcinoma in situ (DCIS) and basal-like breast cancer
Summary
Clinical breast cancer consists of a heterogeneous group of tumors that are only partially distinguishable by morphological presentation. Molecular profiling studies have helped to further resolve the heterogeneity of tumors that are not discernible by morphological evaluation. Five distinct subtypes have been identified by molecular profiling: basal (ER-/PgR-/Her2-/CK5+ that are triple negative for estrogen receptor (ER), progesterone receptor (PgR) and Her2/neu and positive for cytokeratin 5 (CK5), luminal A (ER+/Her2-), luminal B (ER+/ Her2+), Her2-overexpressing, and normal-like [1,2]. The basal subtype of breast cancer represents approximately ~15% of invasive ductal breast cancers. Basal breast cancers present as high grade lesions with areas of necrosis, lymphocytic infiltration, poor nuclear grade and high proliferation rate [3].
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