A Mohs Surgeon’s Perspective on Surface Keratin 1 and Triple-Negative Breast Cancer

As a Mohs surgeon, I have seen how dermatology, oncology, and medicine connect to each other. In dermatology, sometimes we notice the cutaneous manifestations of disease prior to diagnosis of systemic disease. We can have a critical role in early diagnosis and detection by observing subtle changes in the skin. Sometimes we also have cases where the systemic manifestation is found before the skin shows signs of disease.

When I was a dermatology resident, I had the privilege of meeting a Black woman in her 50s who had just been diagnosed with breast cancer. After her initial diagnosis of breast cancer, her oncologist recommended genetic screening. This is a standard practice to identify hereditary cancer syndromes in patients with breast cancer. She was surprised to find out that her genetic screening revealed a mutation in the PTCH1 gene. This gene is associated with Gorlin syndrome, which is also known as basal cell nevus syndrome.

Her oncologist recognized that there was a higher risk of skin cancer with this gene mutation and quickly referred her to our dermatology clinic. Our patient was able to describe that during her life, she had several nonhealing areas on her scalp that often remained hidden beneath her dark curly hair. She assumed that they were sores from relaxing her hair and that her hairdresser would always urge her to find a dermatologist to have these spots evaluated. During the examination, we found numerous pearly, small hyperpigmented papules that were concerning for skin cancer. We biopsied multiple lesions that turned out to be basal cell carcinomas. We were able to address these with a combination of treatments in our Mohs clinic. Her case was a powerful reminder of how an important medical finding in one specialty can illuminate a previously hidden risk in another.

Her story is a testament of why important findings in oncology research can affect us in dermatology. This memory of her came up when reading the recent Scientific Reports article that discovered surface keratin 1 (K1) as a potential molecular target in triple-negative breast cancer (TNBC). Although most important to the breast oncology literature, this scientific finding also holds intriguing promise for dermatologists in cutaneous oncology. This research provides an example of how the dermatology and oncology worlds converge on a shared molecule: K1.

Study Methods

Yao et al explored whether the keratinocyte intracellular structural protein K1 could act as a tumor-selective surface marker in TNBC. The reasoning for this exploration was that if K1 were on the cell surface, it could serve as a site for “docking” during drug delivery. This would allow for peptide-drug conjugates to attack tumor cells while avoiding normal cells. The authors analyzed human breast tissue by using immunohistochemical stains of different subtypes, such as normal breast tissue, TNBC, estrogen receptor positive/progesterone receptor positive (ER+/PR+), and HER2+. The tissue analysis helped them to compare expression of K1 protein across clinical scenarios. Tissues with tumor showed significantly higher K1 expression compared with normal breast tissue. They confirmed the results found in human breast tissue by using 2 normal mammary epithelial cell lines and 3 different human TNBC cell lines (MDA-MB-231, MDA-MB-436, and MDA-MB-468). K1 expression was confirmed by the research team using mass spectrometry, Western blot, and peptide mass fingerprinting. These further provided evidence for the high expression of the K1 protein in TNBC cells.¹

One of the key aspects of this innovative study was to figure out whether the typically intracellular K1 protein was also present on the cell surface. The researchers discovered that K1 is uniformly present on the surface of the TNBC cells using immunofluorescence confocal microscopy. This was an important finding in confirming K1 as a potential target for external ligands.¹Another research finding showed that TNBC-selective peptide, 18-4, was taken up by the cancer cells via a K1-mediated endocytosis pathway. They performed an in vitro assay to confirm the specificity of the peptide and ensure that it did not disrupt the assembly of cytoplasmic keratin filaments, a key indicator that it was binding only to the cell surface K1.

Clinical Implications

The study results also found a positive correlation between EGFR gene expression and KRT1 (the gene for K1) in basal breast cancer subtypes. This finding suggests that the K1 protein may be a cell receptor and help with signaling pathways that drive TNBC progression.¹

Oncologists may be able to use K1 as a biomarker in the future. The immunohistochemical stain analyses showed significantly elevated K1 in human TNBC tissues compared with normal breast tissues. Although K1 was also expressed in ER+/PR+ tissues, its overexpression is most significant for the treatment of TNBC. Historically, the TNBC subtype is very challenging given the lack of targeted therapies. Standard chemotherapy is the backbone of traditional therapy, but outcomes are often poor. Aggressive, higher-stage grade 3 TNBC tumors had 3 times higher expression of K1 compared with grade 2 tumors.¹ High-grade TNBCs also had stronger K1 expression than lower-grade tumors. These findings suggest that K1 could be an important prognostic or diagnostic marker.

This article also helped with strides in therapeutic development because the team showed that the peptide could be selectively delivered to tumor cells by binding to the cell surface K1. Companies could create peptide-drug conjugates or antibody-drug conjugates that target and deliver chemotherapy to TNBC tumors while avoiding harm to healthy tissue. Mouse models have already demonstrated the effectiveness of this approach, and K1-targeting conjugates were 30-fold less toxic to normal breast epithelial cells.¹

Limitations

In this study, there were a few limitations. First, findings from studies using mouse models do not always translate in human clinical trials. This could be a challenge for translating the research findings to medical treatments. Second, there needs to be validation of these findings across diverse and large TNBC cohorts to confirm the applicability of the results. Finally, we do not know the long-term safety of targeting a keratin protein for oncological treatment. There may be benefits but also risks and adverse effects of the medications geared toward keratin protein.

Dermatologist’s Perspective

As a Mohs surgeon and cutaneous oncologist, I think the findings of this paper are intriguing. With a significant role in the epidermal barrier, K1 may be an important link between tumors in the skin and internal disease. In the future, dermatologists could biopsy the skin and provide tissue to analyze for K1 expression. This would help in early detection of breast cancer risk. The research findings in this article could also inspire new research studies to improve our understanding of cell surface keratins in skin cancers such as basal or squamous cell carcinoma.

This research creates a new opportunity for TNBC treatment by validating K1 as a target. TNBC has needed better, more effective improvements, and this research brings us closer to a solution. For both oncology and dermatology, this paper creates a new horizon for how we treat malignancy. This precision oncology means that for breast cancer, K1 provides a possible promise for less toxic and more effective therapies.

For dermatology, it is a hope that molecular targeting strategies could change how we diagnose and treat skin cancers. We should pay attention to this study in dermatology. My patient, who started in a breast oncology clinic but ended up in dermatology, exemplifies this intersection. Her case is a reminder that cancer crosses specialty boundaries, and now our treatment paradigms can too.

Nicole A. Negbenebor, MD, FAAD, is a Mohs micrographic surgery and cutaneous oncology clinical assistant professor and director of the Skin of Color Clinic in the Department of Dermatology at the University of Iowa in Iowa City.

Reference

1. Yao SJ, Amirrad F, Ziaei E, et al. Surface keratin 1, a tumor-selective peptide target in human triple-negative breast cancer. Sci Rep. 2025;15(1):21644. doi:10.1038/s41598-025-05351-z